Novel physiologically active substances

ABSTRACT

Compounds represented by the following general formula (I), pharmacologically acceptable salts thereof or hydrates of the same: (I) wherein W represents  
                 
 
and R 3 , R 7 , R 16 , R 17 , R 20 , R 21  and R 21′  are the same or different and each represents hydrogen, etc. Because of inhibiting angiogenesis and inhibiting the production of VEGF particularly in hypoxia, the compounds (I) are useful as remedies for solid cancer.

TECHNICAL FIELD

The present invention relates to a 12-membered ring macrolide compounduseful as a pharmaceutical agent, a method for producing the same, anduse of the same.

BACKGROUND ART

Conventionally, compounds having cytotoxicity have been used asantitumor agents, and a lot of screenings carrying out usingcytotoxicity as an index. As a result, since most of the conventionalantitumor agents affect cancer cells and, at the same time, normaltissues with active cell proliferation, for example, the bone marrow andintestine epithelium, QOL of patients is not sufficiently improved.

Further, under existing circumstances, antitumor agents have come tohave a rather beneficial effect on treating leukemia, but are notnecessarily effective for solid tumors. Therefore, antitumor agents thatare effective for solid tumors and are highly safe have been stronglydemanded.

Fermentation products of microorganisms have been screened mainly usingcytotoxicity in vitro as an index, in order to use these products asantitumor agents. As a result, many cytotoxic compounds have beendiscovered. However, most of the compounds have been confirmed to showcytotoxic activities only in vitro, and few compounds have been found tohave an antitumor activities in vivo. Furthermore, very few compoundsexhibit efficacy against solid cancers.

DISCLOSURE OF THE INVENTION

An object of the present invention is to discover compounds that showantitumor activities not only in vitro but also in vivo, and haveantitumor activities on solid cancers from fermentation products ofmicroorganism, or their derivatives.

It is considered that tumorgenesis of normal cells mutations of a genein the cell occurs so that an abnormal gene is expressed. In thissituation, the present inventors have conducted extensive studies, basedon the assumption that alteration of gene expression in tumor cells cancause inhibition of proliferation of tumor cells, namely, proliferationof tumor cells can be inhibited by, for example, changing the gene ofongocene or tumor suppressor gene, or changing the gene expression of agene involved in cell cycle. The present inventors have screenedfermentation products of various microorganisms and their derivativesusing VEGF (Vascular Endothelial Growth Factor) production by U251 cellsunder hypoxic stimulation as an index, in the expectation that compoundswhich alter gene expression, in particular, compounds which inhibit VEGFproduction under low hypoxic condition, inhibit angiogenesis by tumorsand, furthermore, exhibit antitumor activity against solid cancers. As aresult, the present inventors have discovered novel physiologicallyactive substances, a 12-membered ring macrolide compound, named 11107,and its analogues, which inhibit VEGF production under low hypoxiccondition in vitro and, further, inhibit proliferation of solid cancercells in vivo.

As a result of further extensive studies, the present inventors havefound that, among the 11107 analogues, 6-deoxy 11107D, in which thehydroxyl group of 11107D at the 6-position is replaced by a hydrogen,and compounds obtained by chemical modification of the 6-deoxy 11107D(hereinafter the compounds are referred to as “6-deoxy 11107Dderivatives”) are stable in an aqueous solution, and that thesederivatives not only inherit the characteristics of stability from of11107D, but also inhibit proliferation of solid tumor cells morepotently in vivo experiments. These findings have led to theaccomplishment of the present invention.

Given as a related art, most structurally similar to the compound of thepresent invention is FD-895, which is a 12-membered ring macrolidecompound (JP-A-04-352783) represented by the formula (XIV):

The above-described gazette discloses that FD-895 has cytotoxic activityin vitro against P388 mouse leukemia cells, L-1210 mouse leukemia cells,and HL-60 human leukemia cells in a RPM-1640 culture medium (Column No.6, Table 2 of the gazette). However, it is reported that FD-895 did notshow antitumor activity in an in vivo experiment using P388 mouseleukemia cells (Seki-Asano M. et al., Antibiotics, 47, 1395-1401, 1994).

Furthermore, as described later, since FD-895 is instable in an aqueoussolution, it is expected to be inappropriate to mix the compound with aninfusion solution upon administered. Therefore, FD-895 does not havesufficient qualities as an antitumor agent.

Therefore, the present invention relates to:

-   1. A compound represented by the formula (I):    wherein W represents    and R³, R⁷, R¹⁶, R¹⁷, R²⁰, R²¹ and R^(21′), the same or different,    independently represent-   1) a hydrogen atom,-   2) a hydroxyl group or oxo group, provided that the oxo group is    limited to an oxo group formed by R³ or R⁷ in combination with a    carbon atom to which R³ or R⁷ is bonded, and an oxo group formed by    R²¹ and R^(21′) together in combination with the carbon atom to    which R²¹ and R^(21′) are bonded,-   3) a C₁ to C₂₂ alkoxy group which may have a substituent,-   4) an unsaturated C₂ to C₂₂ alkoxy group which may have a    substituent,-   5) a C₇ to C₂₂ aralkyloxy group which may have a substituent,-   6) a 5-membered to 14-membered heteroaralkyloxy group which may have    a substituent,-   7) RC(═Y)—O—, wherein Y represents an oxygen atom or sulfur atom,    and R represents

a) a hydrogen atom,

b) a C₁ to C₂₂ alkyl group which may have a substituent,

c) an unsaturated C₂ to C₂₂ alkyl group which may have a substituent,

d) a C₆ to C₁₄ aryl group which may have a substituent,

e) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

f) a C₇ to C₂₂ aralkyl group which may have a substituent,

g) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

h) a C₁ to C₂₂ alkoxy group which may have a substituent,

i) an unsaturated C₂ to C₂₂ alkoxy group which may have a substituent,

j) a C₆ to C₁₄ aryloxy group which may have a substituent,

k) a C₃ to C₁₄ cycloalkyl group which may have a substituent,

l) a 3-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent or

m) a 5-membered to 14-membered heteroaryloxy group which may have asubstituent,

-   8) R^(S1)R^(S2)R^(S3)SiO—, wherein R^(S1), R^(S2) and R^(S3), the    same or different, independently represent

a) a C₁ to C₆ alkyl group or

b) a C₆ to C₁₄ aryl group,

-   9) a halogen atom,-   10) R^(N1)R^(N2)N—R^(M)—, wherein R^(M) represents

a) a single bond,

b) —CO—O—,

c) —SO₂—O—,

d) —CS—O— or

e) —CO—NR^(N3)—, wherein R^(N3) represents a hydrogen atom or a C₁ to C₆alkyl group which may have a substituent, provided that, the leftmostbond in b) to e) is bonded to the nitrogen atom,

R^(N1) and R^(N2), the same or different, independently represent

a) a hydrogen atom,

b) a C₁ to C₂₂ alkyl group which may have a substituent,

c) an unsaturated C₂ to C₂₂ alkyl group which may have a substituent,

d) an aliphatic C₂ to C₂₂ acyl group which may have a substituent,

e) an aromatic C₇ to C₁₅ acyl group which may have a substituent,

f) a C₆ to C₁₄ aryl group which may have a substituent,

g) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

h) a C₇ to C₂₂ aralkyl group which may have a substituent,

i) a C₁ to C₂₂ alkylsulfonyl group which may have a substituent,

j) a C₆ to C₁₄ arylsulfonyl group which may have a substituent,

k) a 3-membered to 14-membered non-aromatic heterocyclic group formed byR^(N1) and R^(N2) together in combination with the nitrogen atom towhich R^(N1) and R^(N2) are bonded, wherein the 3-membered to14-membered non-aromatic heterocyclic group may have a substituent,

l) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

m) a C₃ to C₁₄ cycloalkyl group which may have a substituent or

n) a 3-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent,

-   11) R^(N4)SO₂—O—, wherein R^(N4) represents

a) a C₁ to C₂₂ alkyl group which may have a substituent,

b) a C₆ to C₁₄ aryl group which may have a substituent,

c) a C₁ to C₂₂ alkoxy group which may have a substituent,

d) an unsaturated C₂ to C₂₂ alkoxy group which may have a substituent,

e) a C₆ to C₁₄ aryloxy group which may have a substituent,

f) a 5-membered to 14-membered heteroaryloxy group which may have asubstituent,

g) a C₇ to C₂₂ aralkyloxy group which may have a substituent or

h) a 5-membered to 14-membered heteroaralkyloxy group which may have asubstituent,

-   12) (R^(N5)O)₂PO—O—, wherein R^(N5) represents

a) a C₁ to C₂₂ alkyl group which may have a substituent,

b) an unsaturated C₂ to C₂₂ alkyl group which may have a substituent,

c) a C₆ to C₁₄ aryl group which may have a substituent,

d) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

e) a C₇ to C₂₂ aralkyl group which may have a substituent or

f) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

-   13) (R^(N1)R^(N2)N)₂PO—O—, wherein R^(N1) and R^(N2) are the same as    defined above or-   14) (R^(N1)R^(N2)N)(R^(5N)O)PO—O—, wherein R^(N1), R^(N2) and R^(N5)    are the same as defined above; a pharmacologically acceptable salt    thereof, or a hydrate of those;-   2. The compound according to 1 represented by the formula (I-a):    wherein W is the same as defined above, and R^(3a), R^(7a), R^(16a),    R^(17a), R^(20a), R^(21a) and R^(21a′), the same or different,    independently represent-   1) a hydrogen atom,-   2) a hydroxyl group or oxo group, provided that the oxo group is    limited to an oxo group formed by R^(3a) or R^(7a) in combination    with the carbon atom to which R^(3a) or R^(7a) is bonded, and an oxo    group formed by R^(21a) and R^(21a′) together in combination with a    carbon atom to which R^(21a) and R^(21a′) are bonded,-   3) a C₁ to C₂₂ alkoxy group which may have a substituent,-   4) R^(a)C(═Y^(a))—O—, wherein Y^(a) represents an oxygen atom or    sulfur atom, and R^(a) represents

a) a hydrogen atom,

b) a C₁ to C₂₂ alkyl group which may have a substituent,

c) an unsaturated C₂ to C₂₂ alkyl group which may have a substituent,

d) a C₆ to C₁₄ aryl group which may have a substituent,

e) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

f) a C₇ to C₂₂ aralkyl group which may have a substituent,

g) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

h) a C₁ to C₂₂ alkoxy group which may have a substituent,

i) an unsaturated C₂ to C₂₂ alkoxy group which may have a substituent,

j) a C₆ to C₁₄ aryloxy group which may have a substituent,

k) a C₃ to C₁₄ cycloalkyl group which may have a substituent,

l) a 3-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent or

m) a 5-membered to 14-membered heteroaryloxy group which may have asubstituent,

-   5) R^(aS1)R^(aS2)R^(aS3)SiO—, wherein R^(aS1), R^(aS2) and R^(aS3),    the same or different, independently represent

a) a C₁ to C₆ alkyl group or

b) a C₆ to C₁₄ aryl group or

-   6) R^(aN1)R^(aN2)N—R^(aM)—, wherein R^(aM) represents

a) —CO—O— or

b) —CS—O—, provided that, the leftmost bond in a) or b) is bonded to thenitrogen atom, and

R^(aN1) and R^(aN2), the same or different, independently represent

a) a hydrogen atom,

b) a C₁ to C₂₂ alkyl group which may have a substituent,

c) an unsaturated C₂ to C₂₂ alkyl group which may have a substituent,

d) an aliphatic C₂ to C₂₂ acyl group which may have a substituent,

e) an aromatic C₇ to C₁₅ acyl group which may have a substituent,

f) a C₆ to C₁₄ aryl group which may have a substituent,

g) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

h) a C₇ to C₂₂ aralkyl group which may have a substituent,

i) a C₁ to C₂₂ alkylsulfonyl group which may have a substituent,

j) a C₆ to C₁₄ arylsulfonyl group which may have a substituent,

k) a 3-membered to 14-membered non-aromatic heterocyclic group formed byR^(aN1) and R^(aN2) together in combination with the nitrogen atom towhich R^(aN1) and R^(aN2) are bonded, wherein the 3-membered to14-membered non-aromatic heterocyclic group may have a substituent,

l) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

m) a C₃ to C₁₄ cycloalkyl group which may have a substituent or

n) a 3-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent; a pharmacologically acceptable salt thereof, or ahydrate of those;

-   3. The compound according to 1 represented by the formula (I-b):    wherein W is the same as defined above, and R^(3b), R^(7b), R^(16b),    R^(17b), R^(20b), R^(21b) and R^(21′b), the same or different,    independently represent-   1) a hydrogen atom,-   2) a hydroxyl group or oxo group, provided that the oxo group is    limited to an oxo group formed by R^(3b) or R^(7b) in combination    with the carbon atom to which R^(3b) or R^(7b) is bonded, and an oxo    group formed by R^(21b) and R^(21b′) together in combination with    the carbon atom to which R^(21b) and R^(21b′) are bonded,-   3) a C₁ to C₂₂ alkoxy group which may have a substituent,-   4) R^(b)C(═O)—O—, wherein R^(b) represents

a) a C₁ to C₂₂ alkyl group which may have a substituent,

b) an unsaturated C₂ to C₂₂ alkyl group which may have a substituent,

c) a C₇ to C₂₂ aralkyl group which may have a substituent,

d) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

e) a C₆ to C₁₄ aryloxy group which may have a substituent,

f) a C₃ to C₁₄ cycloalkyl group which may have a substituent or

g) a 3-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent,

-   5) R^(bS1)R^(bS2)R^(bS3)SiO—, wherein R^(bS1), R^(bS2) and R^(bS3),    the same or different, independently represent

a) a C₁ to C₆ alkyl group or

b) a C₆ to C₁₄ aryl group or

-   6) R^(bN1)R^(bN2)N—R^(bM)—, wherein R^(bM) represents

a) —CO—O— or

b) —CS—O—, provided that, the leftmost bond in a) or b) is bonded to thenitrogen atom, and

R^(bN1) and R^(bN2), the same or different, independently represent

a) a hydrogen atom,

b) a C₁ to C₂₂ alkyl group which may have a substituent,

c) a 3-membered to 14-membered non-aromatic heterocyclic group formed byR^(bN1) and R^(bN2) together in combination with the nitrogen atom towhich R^(bN1) and R^(bN2) are bonded, wherein the 3-membered to14-membered non-aromatic heterocyclic group may have a substituent,

d) a C₃ to C₁₄ cycloalkyl group which may have a substituent or

e) a 3-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent; a pharmacologically acceptable salt thereof, orhydrate of those;

-   4. The compound according to 1 represented by the formula (I-c):    wherein W is the same as defined above, and R^(3c), R^(7c), R^(16c),    R^(17c), R^(20c), R^(21c) and R^(21′c), the same or different,    independently represent-   1) a hydrogen atom,-   2) a hydroxyl group or oxo group, provided that the oxo group is    limited to an oxo group formed by R^(3c) or R^(7c) in combination    with the carbon atom to which R^(3c) or R^(7c) is bonded, and an oxo    group formed by R^(21c) and R^(21c′) together in combination with    the carbon atom to which R^(21c) and R^(21c′) are bonded,-   3) R^(c)C(═O)—O—, wherein R^(c) represents a C₁ to C₂₂ alkyl group    which may have a substituent,-   4) R^(cS1)R^(cS2)R^(cS3)SiO—, wherein R^(cS1), R^(cS2) and R^(cS3),    the same or different, independently represent

a) a C₁ to C₆ alkyl group or

b) a C₆ to C₁₄ aryl group or

-   5) R^(cN1)R^(cN2)N—R^(cM)—, wherein R^(cM) represents —CO—O—,    provided that the leftmost bond is bonded to the nitrogen atom, and

R^(cN1) and R^(cN2), the same or different, independently represent

a) a hydrogen atom,

b) a C₁ to C₂₂ alkyl group which may have a substituent,

c) a 3-membered to 14-membered non-aromatic heterocyclic group formed byR^(cN1) and R^(cN2) together in combination with the nitrogen atom towhich R^(cN1) and R^(cN2) are bonded, wherein the 3-membered to14-membered non-aromatic heterocyclic group may have a substituent,

d) a C₃ to C₁₄ cycloalkyl group which may have a substituent or

e) a 3-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent; a pharmacologically acceptable salt thereof, or ahydrate of those;

-   5. The compound according to 1 represented by the formula (I-d):    wherein R^(3d) and R^(16d), the same or different, independently    represent-   1) a hydroxyl group,-   2) a C₁ to C₂₂ alkoxy group which may have a substituent,-   3) an unsaturated C₂ to C₂₂ alkoxy group which may have a    substituent,-   4) a C₇ to C₂₂ aralkyloxy group which may have a substituent,-   5) R^(d)C(═O)—O—, wherein R^(d) represents

a) a hydrogen atom,

b) a C₁ to C₂₂ alkyl group which may have a substituent,

c) an unsaturated C₂ to C₂₂ alkyl group which may have a substituent,

d) a C₆ to C₁₄ aryl group which may have a substituent,

e) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

f) a C₇ to C₂₂ aralkyl group which may have a substituent,

g) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

h) a C₁ to C₂₂ alkoxy group which may have a substituent,

i) an unsaturated C₂ to C₂₂ alkoxy group which may have a substituent,

j) a C₆ to C₁₄ aryloxy group which may have a substituent or

k) a 5-membered to 14-membered heteroaryloxy group which may have asubstituent or

-   6) R^(dN1)R^(dN2)N—CO—O—, wherein R^(dN1) and R^(dN2), the same or    different, independently represent

a) a hydrogen atom,

b) a C₁ to C₂₂ alkyl group which may have a substituent,

c) an unsaturated C₂ to C₂₂ alkyl group which may have a substituent,

d) a C₆ to C₁₄ aryl group which may have a substituent,

e) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

f) a C₇ to C₂₂ aralkyl group which may have a substituent,

g) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

h) a C₃ to C₁₄ cycloalkyl group which may have a substituent,

i) a 3-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent or

j) a 3-membered to 14-membered non-aromatic heterocyclic group formed byR^(dN1) and R^(dN2) together in combination with the nitrogen atom towhich R^(dN1) and R^(dN2) are bonded, wherein the 3-membered to14-membered non-aromatic heterocyclic group may have a substituent andR^(7d) and R^(21d), the same or different, independently represent

-   1) a hydroxyl group,-   2) a C₁ to C₂₂ alkoxy group which may have a substituent,-   3) an unsaturated C₂ to C₂₂ alkoxy group which may have a    substituent,-   4) a C₇ to C₂₂ aralkyloxy group which may have a substituent,-   5) R^(d)C(═O)—O—, wherein R^(d) is the same as defined above,-   6) R^(dN1)R^(dN2)N—CO—O—, wherein R^(dN1) and R^(dN2) are the same    as defined above,-   7) R^(dN1)R^(dN2)N—SO₂—O—, wherein R^(dN1) and R^(dN2) are the same    as defined above,-   8) R^(dN1)R^(dN2)N—CS—O—, wherein R^(dN1) and R^(dN2) are the same    as defined above,-   9) R^(dN4)—SO₂—O—, wherein R^(dN4) represents

a) a C₁ to C₂₂ alkyl group which may have a substituent,

b) a C₆ to C₁₄ aryl group which may have a substituent,

c) a C₁ to C₂₂ alkoxy group which may have a substituent,

d) an unsaturated C₂ to C₂₂ alkoxy group which may have a substituent,

e) a C₆ to C₁₄ aryloxy group which may have a substituent,

f) a 5-membered to 14-membered heteroaryloxy group which may have asubstituent,

g) a C₇ to C₂₂ aralkyloxy group which may have a substituent or

h) a 5-membered to 14-membered heteroaralkyloxy group which may have asubstituent,

-   10) (R^(dN5)O)₂PO—O—, wherein R^(dN5) represents

a) a C₁ to C₂₂ alkyl group which may have a substituent,

b) an unsaturated C₂ to C₂₂ alkyl group which may have a substituent,

c) a C₆ to C₁₄ aryl group which may have a substituent,

d) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

e) a C₇ to C₂₂ aralkyl group which may have a substituent or

f) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

-   11) (R^(dN1)R^(dN2)N)₂PO—O—, wherein R^(dN1) and R^(dN2) are the    same as defined above or-   12) (R^(dN1)R^(dN2)N)(R^(dN5)O)PO—O—, wherein R^(dN1), R^(dN2) and    R^(dN3) are the same as defined above; a pharmacologically    acceptable salt thereof, or a hydrate of those;-   6. The compound according to 1, wherein R⁷ and/or R²¹ are    independently represented by RC(═Y)—O—, wherein Y and R are the same    as defined above, or R^(N1)R^(N2)N—R^(M′)—, wherein R^(M′)    represents

a) —CO—O— or

b) —CS—O—, provided that, the leftmost bond in a) or b) is bonded to thenitrogen atom, and

R^(N1) and R^(N2) are the same as defined above; a pharmacologicallyacceptable salt thereof, or a hydrate of those;

-   7. The compound according to 5 represented by the formula (I-e):    wherein R^(3e), R^(16e) and R^(21e), the same or different,    independently represent-   1) a hydroxyl group,-   2) a C₁ to C₂₂ alkoxy group which may have a substituent,-   3) an unsaturated C₂ to C₂₂ alkoxy group which may have a    substituent,-   4) a C₇ to C₂₂ aralkyloxy group which may have a substituent,-   5) an aliphatic C₂ to C₆ acyl group which may have a substituent or-   6) R^(eN1)R^(eN2)N—CO—O—, wherein R^(eN1) and R^(eN2) independently    represent

a) a hydrogen atom or

b) a C₁ to C₆ alkyl group which may have a substituent and

-   R^(7e) represents R^(e)—C(═Y^(e))—O—, wherein Y^(e) represents an    oxygen atom or sulfur atom, and R^(e), the same or different,    represents

a) a hydrogen atom,

b) a C₁ to C₂₂ alkyl group which may have a substituent,

c) a C₆ to C₁₄ aryl group which may have a substituent,

d) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

e) a C₇ to C₁₀ aralkyl group which may have a substituent,

f) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

g) a 3-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent,

h) a group of the formula (III):

wherein A) n represents an integer of 0 to 4,

-   X_(e) represents

i) —CHR^(eN4)—,

ii) —NR^(eN5)—,

iii) —O—,

iv) —S—,

v) —SO— or

vi) —SO₂—,

-   R^(eN1) represents

i) a hydrogen atom or

ii) a C₁ to C₆ alkyl group which may have a substituent,

-   R^(eN2) represents

i) a hydrogen atom or

ii) a C₁ to C₆ alkyl group which may have a substituent,

-   R^(eN3) and R^(eN4), the same or different, independently represent

i) a hydrogen atom,

ii) a C₁ to C₆ alkyl group which may have a substituent,

iii) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent,

iv) a C₆ to C₁₄ aryl group which may have a substituent,

v) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

vi) a C₇ to C₁₀ aralkyl group which may have a substituent,

vii) a C₃ to C₈ cycloalkyl group which may have a substituent,

viii) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

ix) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

x) a 5-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent,

xi) —NR^(eN6)R^(eN7), wherein R^(eN6) and R^(eN7), the same ordifferent, independently represent a hydrogen atom or a C₁ to C₆ alkylgroup which may have a substituent or

xii) a 5-membered to 14-membered non-aromatic heterocyclic group formedby R^(eN3) and R^(eN4) together in combination with the carbon atom towhich R^(eN3) and R^(eN4) are bonded, wherein the 5-membered to14-membered non-aromatic heterocyclic group may have a substituent and

-   R^(eN5) represents

i) a hydrogen atom,

ii) a C₁ to C₆ alkyl group which may have a substituent,

iii) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent,

iv) a C₆ to C₁₄ aryl group which may have a substituent,

v) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

vi) a C₇ to C₁₀ aralkyl group which may have a substituent,

vii) a C₃ to C₈ cycloalkyl group which may have a substituent,

viii) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

ix) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

x) a 5-membered to 14-membered non-aromatic heterocyclic group which mayhave a substituent or

xi) a 5-membered to 14-membered non-aromatic heterocyclic group formedby R^(eN3) and R^(eN5) together in combination with the nitrogen atom towhich R^(eN3) and R^(eN5) are bonded, wherein the 5-membered to14-membered non-aromatic heterocyclic group may have a substituent,

-   B)

X_(e), n, R^(eN3), R^(eN4) and R^(eN5) independently represent the samegroup as defined above, and R^(eN1) and R^(eN2) independently representa 5-membered to 14-membered non-aromatic heterocyclic group formed byR^(eN1) and R^(eN2) together, wherein the 5-membered to 14-memberednon-aromatic heterocyclic group may have a substituent,

-   C)

X_(e), n, R^(eN2), R^(eN4) and R^(eN5) independently represent the samegroup as defined above, and R^(eN1) and R^(eN2) independently representa 5-membered to 14-membered non-aromatic heterocyclic group formed byR^(eN1) and R^(eN2) together, wherein the 5-membered to 14-memberednon-aromatic heterocyclic group may have a substituent or

-   D)

X_(e), n, R^(eN1), R^(eN4) and R^(eN5) independently represent the samegroup as defined above, and R^(eN2) and R^(eN3) independently representa 5-membered to 14-membered non-aromatic heterocyclic group formed byR^(eN2) and R^(eN3) together, wherein the 5-membered to 14-memberednon-aromatic heterocyclic group may have a substituent or

i) a group of the formula (IV):

-   wherein R^(eN8) and R^(eN9), the same or different, independently    represent

i) a hydrogen atom,

ii) a C₁ to C₆ alkyl group which may have a substituent,

iii) a C₆ to C₁₄ aryl group which may have a substituent,

iv) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

v) a C₇ to C₁₀ aralkyl group which may have a substituent or

vi) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent; a pharmacologically acceptable salt thereof, or a hydrateof those;

-   8. The compound according to 5, wherein R^(7e) and/or R^(21e) are    independently represented by R^(e1)C(═Y^(e1))—O—, wherein Y^(e1)    represents an oxygen atom or sulfur atom, and R^(e1) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) a C₆ to C₁₀ aryl group which may have a substituent,

4) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

5) a C₇ to C₁₀ aralkyl group which may have a substituent or

6) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent; a pharmacologically acceptable salt thereof, or a hydrateof those;

-   9. The compound according to 5, wherein R^(7e) and/or R^(21e) are    independently represented by R^(e2)C(═Y^(e2))—O—, wherein Y^(e2)    represents an oxygen atom or sulfur atom, and R^(e2) represents a    group of the formula (III′):    wherein A) n represents an integer of 0 to 4,-   X₁ represents

1) —CHR^(eN13)—,

2) —NR^(eN14)—,

3) —O—,

4) —S—,

5) —SO— or

6) —SO₂—,

-   R^(eN10) and R^(eN11), the same or different, independently    represent

1) a hydrogen atom or

2) a C₁ to C₆ alkyl group which may have a substituent,

-   R^(eN12) and R^(eN13), the same or different, independently    represent

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent,

4) a C₆ to C₁₄ aryl group which may have a substituent,

5) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

6) a C₇ to C₁₀ aralkyl group which may have a substituent,

7) a C₃ to C₈ cycloalkyl group which may have a substituent,

8) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

9) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

10) a 5-membered to 14-membered non-aromatic heterocyclic group whichmay have a substituent,

11) —NR^(eN15)R^(eN16), wherein R^(eN15) and R^(eN16), the same ordifferent, independently represent a hydrogen atom or a C₁ to C₆ alkylgroup which may have a substituent or

12) a 5-membered to 14-membered non-aromatic heterocyclic group formedby R^(eN12) and R^(eN13) together, wherein the 5-membered to 14-memberednon-aromatic heterocyclic group may have a substituent and

-   R^(eN14) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent,

4) a C₆ to C₁₄ aryl group which may have a substituent,

5) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

6) a C₇ to C₁₀ aralkyl group which may have a substituent,

7) a C₃ to C₈ cycloalkyl group which may have a substituent,

8) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

9) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

10) a 5-membered to 14-membered non-aromatic heterocyclic group whichmay have a substituent,

11) a 5-membered to 14-membered non-aromatic heterocyclic group formedtogether by the nitrogen atom to which R^(eN14) is bonded, and onesubstituent selected from the group consisting of R^(eN10), R^(eN11) andR^(eN12) wherein the 5-membered to 14-membered non-aromatic heterocyclicgroup may have a substituent or

12) a 5-membered to 14-membered non-aromatic heterocyclic group formedtogether by the nitrogen atom to which R^(eN14) is bonded, and twosubstituents selected from the group consisting of R^(eN10), R^(eN11)and R^(eN12) wherein the 5-membered to 14-membered non-aromaticheterocyclic group may have a substituent or

-   B)

n, X₁, R^(eN11), R^(eN13) and R^(eN14) are the same as defined above,and R^(eN10) and R^(eN12) together form a 5-membered to 14-memberednon-aromatic heterocyclic group formed by R^(eN10) and R^(eN12), whereinthe 5-membered to 14-membered non-aromatic heterocyclic group may have asubstituent; a pharmacologically acceptable salt thereof, or a hydrateof those;

10. The compound according to 5, wherein X₁ represents —NR^(eN14)—,wherein NR^(eN14) is the same as defined above; a pharmacologicallyacceptable salt thereof, or a hydrate of those;

11. The compound according to 5, wherein R^(7e) and/or R^(21e)independently represent R^(e3)C(═Ye³)—O—, wherein Y^(e3) represents anoxygen atom or sulfur atom, and R^(e3) represents a group of the formula(V):

wherein n₁ represents an integer of 0 to 6,

-   R^(eN17) represents

1) a hydrogen atom or

2) a C₁ to C₆ alkyl group which may have a substituent and

-   R^(eN18) represents

1) a hydrogen atom,

2) an amino group which may have a substituent,

3) a pyridyl group which may have a substituent,

4) a pyrrolidin-1-yl group which may have a substituent,

5) a piperidin-1-yl group which may have a substituent,

6) a morpholin-4-yl group which may have a substituent or

7) a piperazin-1-yl group which may have a substituent; apharmacologically acceptable salt thereof, or a hydrate of those;

12. The compound according to 5, wherein R^(7e) and/or R^(21e)independently represent R^(e4)CO—O—, wherein R^(e4) represents a groupof the formula (VI):

wherein n₂ and n₃, the same or different, independently represent aninteger of 0 to 4,

-   X₂ represents

1) —CHR^(eN21)—,

2) —NR^(eN22)—,

3) —O—,

4) —S—,

5) —SO— or

6) —SO₂—,

-   R^(eN19) represents

1) a hydrogen atom or

2) a C₁ to C₆ alkyl group which may have a substituent,

-   R^(eN20) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) a C₆ to C₁₄ aryl group which may have a substituent or

4) a C₇ to C₁₀ aralkyl group which may have a substituent,

-   R^(eN21) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent,

4) a C₆ to C₁₄ aryl group which may have a substituent,

5) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

6) a C₇ to C₁₀ aralkyl group which may have a substituent,

7) a C₃ to C₈ cycloalkyl group which may have a substituent,

8) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

9) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

10) —NR^(eN23)R^(eN24), wherein R^(eN23) and R^(eN24), the same ordifferent, independently represent a hydrogen atom or a C₁ to C₆ alkylgroup which may have a substituent or

11) a 5-membered to 14-membered non-aromatic heterocyclic group whichmay have a substituent and

-   R^(eN22) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent,

4) a C₆ to C₁₄ aryl group which may have a substituent,

5) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

6) a C₇ to C₁₀ aralkyl group which may have a substituent,

7) a C₃ to C₈ cycloalkyl group which may have a substituent,

8) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

9) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent or

10) a 5-membered to 14-membered non-aromatic heterocyclic group whichmay have a substituent; a pharmacologically acceptable salt thereof, ora hydrate of those;

13. The compound according to 5, wherein R^(7e) and/or R^(21e)independently represent R^(e5)CO—O—, wherein R^(e5) represents a groupof the formula (VII):

wherein n₄ represents 1 or 2,

-   R^(eN25) represents

1) a hydrogen atom or

2) a C₁ to C₆ alkyl group which may have a substituent and

-   R^(eN26) represents

1) a hydrogen atom or

2) a C₁ to C₆ alkyl group which may have a substituent; apharmacologically acceptable salt thereof, or a hydrate of those;

14. The compound according to 5, wherein R^(7e) and/or R^(21e)independently represent R^(e6)CO—O—, wherein R^(e6) represents a groupof the formula (VIII):

wherein n₂ and n₃, the same or different, independently represent aninteger of 0 to 4,

-   X₃ represents

1) —CHR^(eN29)—,

2) —NR^(eN30)—,

3) —O—,

4) —S—,

5) —SO— or

6) —SO₂—,

-   R^(eN27) represents

1) a hydrogen atom or

2) a C₁ to C₆ alkyl group which may have a substituent,

-   R^(eN28) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) a C₆ to C₁₄ aryl group which may have a substituent or

4) a C₇ to C₁₀ aralkyl group which may have a substituent,

-   R^(eN29) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent,

4) a C₁ to C₆ alkoxy group which may have a substituent,

5) a C₆ to C₁₄ aryl group which may have a substituent,

6) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

7) a C₇ to C₁₀ aralkyl group which may have a substituent,

8) a C₃ to C₈ cycloalkyl group which may have a substituent,

9) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

10) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent,

11) —NR^(eN31)R^(eN32), wherein R^(eN31) and R^(eN32), the same ordifferent, independently represent a hydrogen atom or a C₁ to C₆ alkylgroup which may have a substituent or form a 5-membered to 14-memberednon-aromatic heterocyclic group together with the nitrogen atom to whichR^(eN31) and R^(eN32) are bonded or

12) a 5-membered to 14-membered non-aromatic heterocyclic group whichmay have a substituent and

-   R^(eN30) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent,

4) a C₆ to C₁₄ aryl group which may have a. substituent,

5) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

6) a C₇ to C₁₀ aralkyl group which may have a substituent,

7) a C₃ to C₈ cycloalkyl group which may have a substituent,

8) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

9) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent or

10) a 5-membered to 14-membered non-aromatic heterocyclic group whichmay have a substituent; a pharmacologically acceptable salt thereof, ora hydrate of those;

15. The compound according to 5, wherein R^(7e) and/or R^(21e)independently represent R^(e7)CO—O—, wherein R^(e7) represents a groupof the formula (IX):

wherein n₅ represents an integer of 1 to 3, and

-   R^(eN33) represents

1) an amino group,

2) an amino group which may have a substituent,

3) a pyrrolidin-1-yl group which may have a substituent,

4) a piperidin-1-yl group which may have a substituent or

5) a morpholin-4-yl group which may have a substituent; apharmacologically acceptable salt thereof, or a hydrate of those;

16. The compound according to 5, wherein R^(7e) and/or R^(21e)independently represent R^(e8)CO—O—, wherein R^(e8) represents a groupof the formula (X):

wherein n₅ represents an integer of 1 to 3,

-   R^(eN34) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) a C₆ to C₁₄ aryl group which may have a substituent or

4) a C₇ to C₁₀ aralkyl group which may have a substituent and

-   R^(eN35) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) a C₃ to C₈ cycloalkyl group which may have a substituent,

4) a 3-membered to 8-membered non-aromatic heterocyclic group which mayhave a substituent,

5) a C₆ to C₁₄ aryl group which may have a substituent,

6) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

7) a C₇ to C₁₀ aralkyl group which may have a substituent,

8) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent or

9) a C₄ to C₉ cycloalkylalkyl group which may have a substituent; apharmacologically acceptable salt thereof, or a hydrate of those;

17. The compound according to 5, wherein R^(7e) and/or R^(21e)independently represent R^(e9)CO—O—, wherein R^(e9) represents a groupof the formula (XI):

wherein n₅ represents an integer of 1 to 3, and

-   R^(eN36) represents

1) a hydrogen atom,

2) a C₁ to C₈ alkyl group which may have a substituent,

3) a C₃ to C₆ cycloalkyl group which may have a substituent,

4) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

5) a C₇ to C₁₀ aralkyl group which may have a substituent,

6) a pyridyl group which may have a substituent or

7) a tetrahydropyranyl group which may have a substituent; apharmacologically acceptable salt thereof, or a hydrate of those;

18. The compound according to 5, wherein R^(7e) and/or R^(21e)independently represent R^(e10)CO—O—, wherein

-   R^(e10) represents a group of the formula (XII):    wherein m₁, m₂, m₃ and m₄, the same or different, independently    represent 0 or 1,-   n₅ represents an integer of 1 to 3, and-   R^(eN37) represents

1) a hydrogen atom,

2) a C₁ to C₆ alkyl group which may have a substituent,

3) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent,

4) a C₆ to C₁₄ aryl group which may have a substituent,

5) a 5-membered to 14-membered heteroaryl group which may have asubstituent,

6) a C₇ to C₁₀ aralkyl group which may have a substituent,

7) a C₃ to C₈ cycloalkyl group which may have a substituent,

8) a C₄ to C₉ cycloalkylalkyl group which may have a substituent,

9) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent or

10) a 5-membered to 14-membered non-aromatic heterocyclic group whichmay have a substituent; a pharmacologically acceptable salt thereof, ora hydrate of those;

19. The compound according to 5, wherein R^(7e) and/or R^(21e)independently represent R^(e11)CO—O—, wherein R^(e11) represents a groupof the formula (XIII):

wherein m₅ represents an integer of 1 to 3, and n₅ represents 2 or 3; apharmacologically acceptable salt thereof, or a hydrate of those;

20. The compound according to 5, wherein R^(7e) and/or R^(2 e)independently represent R^(e12)CO—O—, wherein R^(e12) represents a groupselected from a group consisting of:

or a group selected from a group consisting of

and both of which may have a substituent on the ring; apharmacologically acceptable salt thereof, or a hydrate of those;

-   21. The compound according to 1, wherein R¹⁶ is a hydroxyl group; a    pharmacologically acceptable salt thereof, or a hydrate of those;-   22. The compound according to 1, wherein-   [1] W is-   R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶,    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom,-   [2] W is-   R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶,    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom,-   [3] W is-   R³, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom,-   [4] W is-   R²¹ and R^(21′) form an oxo group together with the carbon atom to    which R²¹ and R^(21′) are bonded, R³, R¹⁶ and R²⁰ are a hydroxyl    group, R⁷ is an acetoxy group, and R¹⁷ is a hydrogen atom,-   [5] W is-   R³, R¹⁶, R²⁰ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group,    and R¹⁷ and R^(21′) are a hydrogen atom,-   [6] W is-   R³, R⁷, R¹⁶ and R²¹ are a hydroxyl group, and R¹⁷, R²⁰ and R^(21′)    are a hydrogen atom,-   [7] W is-   R³, R¹⁷, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group,    and R²⁰ and R^(21′) are a hydrogen atom or-   [8] W is-   R²¹ and R^(21′) form an oxo group together with the carbon atom to    which R²¹ and R^(21′) are bonded, R³ and R¹⁶ are a hydroxyl group,    R⁷ is an acetoxy group, and R¹⁷ and R²⁰ are a hydrogen atom; a    pharmacologically acceptable salt thereof, or a hydrate of those;-   23. The compound according to 1, which is-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 18),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 19),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 21),-   (8E,12E,14E)-7-((4-ethylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 24),    (8E,12E,14E)-7-(N-(3-(N′,N′-dimethylamino)propyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 27),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 28),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 29),-   (8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 39),    (8E,12E,14E)-3,16,21-trihydroxy-7-((4-(4-hydroxypiperidin-1-yl)piperidin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 40),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(morpholin-4-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 42),-   (8E,12E,14E)-7-((4-ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 43),    (8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 44),-   (8E,12E,14E)-3,16,21-trihydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 49),-   (8E,12E,14E)-7-(N-(2-(N′,N′-dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 50),-   (8E,12E,14E)-7-(N-(2-(N′,N′-dimethylamino)ethyl)carbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 51) or-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 55);-   24. The compound according to 1, which is-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 29),-   (8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 39),-   (8E,12E,14E)-7-((4-ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 43),    (8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 44) or-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 55);-   25. A medicine comprising the compound according to any one of 1 to    24, a pharmacologically acceptable salt thereof, or a hydrate of    those as an active ingredient;-   26. A pharmaceutical composition comprising the compound according    to any one of 1 to 24, a pharmacologically acceptable salt thereof,    or a hydrate of those as an active ingredient;-   27. The medicine according to 25 as an agent for preventing or    treating a disease for which gene expression control is effective;-   28. The medicine according to 25 as an agent for preventing or    treating a disease for which suppression of VEGF production is    effective;-   29. The medicine according to 25 as an agent for preventing or    treating a disease for which an antiangiogenic effect is effective;-   30. The medicine according to 25 as an angiogenesis inhibitor;-   31. The medicine according to 25 as an antitumor agent;-   32. The medicine according to 25 as a therapeutic agent for treating    hemangioma;-   33. The medicine according to 25 as a cancer metastasis inhibitor;-   34. The medicine according to 25 as a therapeutic agent for treating    retinal neovascularization or diabetic retinopathy;-   35. The medicine according to 25 as a therapeutic agent for treating    inflammatory disease;-   36. The medicine according to 25 as a therapeutic agent for treating    inflammatory diseases consisting of deforamant arthritis, rheumatoid    arthritis, psoriasis, and delayed hypersensitive reaction;-   37. The medicine according to 25 as a therapeutic agent for treating    atherosclerosis;-   38. The medicine according to 25 as a therapeutic agent for treating    a solid cancer;-   39. The medicine according to 38, wherein the solid tumor is lung    cancer, brain tumor, breast cancer, prostate cancer, ovarian cancer,    colon cancer or melanoma;-   40. The medicine according to 25 as a therapeutic agent for treating    leukemia;-   41. The medicine according to 25 as an antitumor agent based on gene    expression control;-   42. The medicine according to 25 as an antitumor agent based on VEGF    suppression of production;-   43. The medicine according to 25 as an antitumor agent based on an    effect of angiogenesis inhibition;-   44. A method for preventing or treating a disease for which gene    expression control is effective, comprising administering a    pharmacologically effective dose of the medicine according to 25 to    a patient.-   45. A method for preventing or treating a disease for which    suppression of VEGF production is effective, comprising    administering a pharmacologically effective dose of the medicine    according to 25 to a patient;-   46. A method for preventing or treating a disease for which    angiogenesis inhibition is effective, comprising administering a    pharmacologically effective dose of the medicine according to 25 to    a patient;-   47. Use of the compound according to any one of 1 to 24, a    pharmacologically acceptable salt thereof or a hydrate of those, for    manufacturing an agent for preventing or treating a disease for    which gene expression control is effective;-   48. Use of the compound according to any one of 1 to 24, a    pharmacologically acceptable salt thereof or a hydrate of those, for    manufacturing an agent for preventing or treating a disease for    which suppression of VEGF production is effective;-   49. Use of the compound according to any of 1 to 24, a    pharmacologically acceptable salt thereof or a hydrate of those, for    manufacturing an agent for preventing or treating a disease for    which angiogenesis inhibition is effective;-   50. Use of the compound according to any one of 1 to 24, a    pharmacologically acceptable salt thereof or a hydrate of those, for    manufacuturing an agent for preventing or treating a solid cancer;-   51. A method for producing a 6-deoxy 11107 compound, characterized    in that the method comprises culturing a microorganism belonging to    the genus Streptomyces, which is capable of producing a compound of    the formula (I):    wherein [1] W is-   R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶,    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom or-   [2] W is-   R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶,    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom; and collecting the    compound as defined in [1] or [2] (hereinafter referred to as    “6-deoxy 11107 compound”) from the culture;-   52. Streptomyces sp. strain A-1543 (FERM BP-8442) that is capable of    producing the 6-deoxy 11107 compound according to 51;-   53. A method for producing a 6-deoxy compound by biologically    converting for compound of the formula (I):    wherein [1] W is-   R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶,    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom (hereinafter referred to as    “6-deoxy 11107B”) into a compound of the formula (I), wherein-   [3] W is-   R³, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom,-   [4] W is-   R²¹ and R^(21′) form an oxo group together with the carbon atom to    which R²¹ and R^(21′) are bonded, R³, R¹⁶ and R²⁰ are a hydroxyl    group, R⁷ is an acetoxy group, and R¹⁷ is a hydrogen atom,-   [5] W is-   R³, R¹⁶, R²⁰ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group,    and R¹⁷ and R^(21′) are a hydrogen atom,-   [6] W is-   R³, R⁷, R¹⁶ and R²¹ are a hydroxyl group, and R¹⁷, R²⁰ and R²¹′ are    a hydrogen atom,-   [7] W is-   R³, R¹⁷, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group,    and R²⁰ and R^(21′) are a hydrogen atom or-   [8] W is-   R²¹ and R^(21′) form an oxo group together with the carbon atom to    which R²¹ and R^(21′) are bonded, R³ and R¹⁶ are a hydroxyl group,    R⁷ is an acetoxy group, and R¹⁷ and R²⁰ are a hydrogen atom (these    compounds are hereinafter referred to as “6-deoxy compounds”),    comprising-   1) a step that can conduct the biological conversion, the step of    incubating 6-deoxy 11107B in the presence of a culture solution of a    strain selected from microorganisms belonging to bacteria or a    product prepared from culture cells of the strain, and-   2) collecting a 6-deoxy compound from the incubated solution;

54. The method according to 53, wherein the microorganism belonging tobacteria is strain A-1544 (FERM BP-8446) or strain A-1545 (FERMBP-8447); and

55. Strain A-1544 (FERM BP-8446) or strain A-1545 (FERM BP-8447) whichis capable of converting 6-deoxy 11107B into a 6-deoxy compound.

BEST MODE FOR CARRYING OUT THE INVENTION

Various terms, symbols, and the like used in the present specificationwill be described.

In the present specification, a chemical formula of the compound of thepresent invention is illustrated as a plan chemical formula forconvenience. However, the present invention can include given isomersderived from the chemical formula. The present invention can include allisomers and mixtures of such as geometric isomers which are generatedfrom the confirguration of the compound, optical isomers based onasymmetric carbon, rotamers, stereoisomers, and tautomers, and mixturesof these isomers. The present invention is not limited to theexpediential description of a chemical formula, and can include any oneof the above-described isomers or mixtures thereof. Accordingly, thecompound of the present invention exist as an optically active substanceor racemate when the compound has an asymmetric carbon atom in themolecule, and both the optically active substance and the racemate areincluded in the present invention. Although crystal polymorphs of thecompound may be present, the compound is not limited to only one crystalform and may be present as a single crystal form or a mixture ofmultiple crystal forms. The compound of the formula (I) of the presentinvention or its salt may be an anhydrate or hydrate. Both an anhydrateand a hydrate are included in the present invention. A metabolitegenerated by decomposition of the compound of the formula (I) of thepresent invention in vivo, and a prodrug of the compound of the formula(I) of the present invention or its salt are included in the presentinvention.

The “halogen atom” used in the specification of the present applicationrefers to a fluorine atom, chlorine atom, bromine atom and iodine atom.For example, a fluorine atom, chlorine atom and bromine atom arepreferable. Of these, for example, a fluorine atom and chlorine atom aretypically preferable.

The “C₁ to C₂₂ alkyl group” used in the specification of the presentapplication refers to a linear or branched alkyl group having 1 to 22carbon atoms. Examples include a methyl group, ethyl group, n-propylgroup, iso-propyl group, n-butyl group, iso-butyl group, sec-butylgroup, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group,1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group,n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropylgroup, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutylgroup, 2-methylpentyl group, 3-methylpentyl group, n-heptyl group,n-octyl group, n-nonyl group and n-decyl group.

The “C₁ to C₂₂ alkyl group” preferably refers to a linear or branchedalkyl group having 1 to 6 carbon atoms. Examples include a methyl group,ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butylgroup, sec-butyl group, tert-butyl group and n-pentyl group. Of these,for example, a methyl group, ethyl group, propyl group, iso-propylgroup, n-butyl group, iso-butyl group and tert-butyl group arepreferable.

The “unsaturated C₂ to C₂₂ alkyl group” used in the specification of thepresent application refers to a linear or branched alkenyl group having2 to 22 carbon atoms or a linear or branched alkynyl group having 2 to22 carbon atoms. Examples include a vinyl group, allyl group, 1-propenylgroup, iso-propenyl group, 2-methyl-1-propenyl group,2-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenylgroup, 1-pentenyl group, 1-hexenyl group, 1,3-hexanedienyl group,1,5-hexanedienyl group, ethynyl group, 1-propynyl group, 2-propynylgroup, 1-butynyl group, 2-butynyl group, 3-butynyl group,1-ethynyl-2-propynyl group, 2-methyl-3-butynyl group, 1-pentynyl group,1-hexynyl group, 1,3-hexanediynyl group and 1,5-hexanediynyl group. The“unsaturated C₂ to C₂₂ alkyl group” preferably refers to a linear orbranched alkenyl group having 2 to 10 carbon atoms or a linear orbranched alkynyl group having 2 to 10 carbon atoms. Preferable examplesinclude a vinyl group, allyl group, 1-propenyl group, isopropenyl group,3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group, ethynylgroup, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynylgroup, 3-butynyl group and 3-methyl-1-propynyl group.

The “C₆ to C₁₄ aryl group” used in the specification of the presentapplication refers to an aromatic hydrocarbon group composed of 6 to 14carbon atoms and includes a monocyclic group and condensed ring such asa bicyclic group, or tricyclic group. Examples include a phenyl group,indenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl group,heptalenyl group, indacenyl group, acenaphthyl group, fluorenyl group,phenalenyl group, phenanthrenyl group and anthracenyl group. Forexample, a phenyl group, 1-naphthyl group, and 2-naphthyl group arepreferable.

The “5-membered to 14-membered heteroaryl group” in the specification ofthe present application refers to a monocyclic, bicyclic, or tricyclic5-membered to 14-membered aromatic heterocyclic group containing one ormore hetero atoms selected from the group consisting of a nitrogen atom,sulfur atom and oxygen atom. Preferable examples includenitrogen-containing aromatic heterocyclic group such as a pyrrolylgroup, pyridinyl group, pyridazinyl group, pyrimidinyl group, pyrazinylgroup, triazolyl group, tetrazolyl group, benzotriazolyl group,pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group,isoindolyl group, indolizinyl group, purinyl group, indazolyl group,quinolinyl group, isoquinolinyl group, quinolizinyl group, phthalazinylgroup, naphthylidinyl group, quinoxalinyl group, quinazolinyl group,cinnolinyl group, pteridinyl group, imidazotriazinyl group,pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group,carbazolyl group, carbazolinyl group, perimidinyl group, phenanthrolinylgroup, phenazinyl group, imidazopyridinyl group, imidazopyrimidinylgroup, pyrazolopyridinyl group and pyrazolopyridinyl group;sulfur-containing aromatic heterocyclic group such as a thienyl groupand benzothienyl group; oxygen-containing aromatic heterocyclic groupsuch as a furyl group, pyranyl group, cyclopentapyranyl group,benzofuryl group and isobenzofuryl group; and aromatic heterocyclicgroups containing two or more different hetero atoms such as a thiazolylgroup, isothiazolyl group, benzothiazolyl group, benzothiadiazolylgroup, phenothiazinyl group, isoxazolyl group, furazanyl group,phenoxazinyl group, oxazolyl group, isoxazoyl group, benzoxazolyl group,oxadiazolyl group, pyrazolooxazolyl group, imidazothiazolyl group,thienofuranyl group, furopyrrolyl group and pyridoxazinyl group. Forexample, a thienyl group, furyl group, pyridinyl group, pyridazinylgroup, pyrimidinyl-group and pyrazinyl group are preferable.

The “3-membered to 14-membered non-aromatic heterocyclic group” in thespecification of the present application refers to a monocyclic,bicyclic, or tricyclic 3-membered to 14-membered non-aromaticheterocyclic group, which may contain one or more hetero atoms selectedfrom the group consisting of a nitrogen atom, sulfur atom and oxygenatom. Preferable examples include an aziridinyl group, azetidyl group,pyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinylgroup, homopiperidinyl group, homopiperazinyl group, imidazolyl group,pyrazolidinyl group, imidazolidinyl group, morpholinyl group,thiomorpholinyl group, imidazolinyl group, oxazolinyl group,2,5-diazabicyclo[2.2.1]heptyl group, 2,5-diazabicyclo[2.2.2]octyl group,3,8-diazabicyclo[3.2.1]octyl group, 1,4-diazabicyclo[4.3.0]nonyl group,quinuclidinyl group, tetrahydrofuranyl group and tetrahydrothiophenylgroup. The above-described non-aromatic heterocyclic groups include agroup derived from a pyridone ring, and a non-aromatic condensed ring(for example, a group derived from a phthalimide ring, succinimide ringor the like).

The “C₇ to C₂₂ aralkyl group” used in the specification of the presentapplication refers to a group of the above-defined “C₁ to C₂₂ alkylgroup” on which the above-defined “C₆ to C₁₄ aryl group” is substitutedas a substituent for replaceble moiety thereof. Specific examplesinclude a benzyl group, phenethyl group, 3-phenylpropyl group,4-phenylbutyl group, 1-naphthylmethyl group and 2-naphthylmethyl group.An aralkyl group having 7 to 10 carbon atoms, for example, a benzylgroup or phenethyl group, is preferable.

The “5-membered to 14-membered heteroaralkyl group” used in thespecification of the present application refers a group of theabove-defined “C₁ to C₂₂ alkyl group” having the above-defined“5-membered to 14-membered heteroaryl group” as a substituent. Specificexamples include a thienylmethyl group, furylmethyl group,pyridinylmethyl group, pyridazinylmethyl group, pyrimidinylmethyl group,and pyrazinyl methyl group. For example, a thienylmethyl group,furylmethyl group and pyridinylmethyl group are preferable.

The “C₃ to C₁₄ cycloalkyl group” used in the specification of thepresent application refers to a cycloalkyl group composed of 3 to 14carbon atoms. Examples of the suitable group include a cyclopropylgroup, cyclobutyl group, cyclopentyl group, cyclohexyl group,cycloheptyl group and cyclooctyl group. For example, a cyclopentylgroup, a cyclohexyl group, cycloheptyl group and cyclooctyl group arepreferable.

The “C₄ to C₉ cycloalkylalkyl group” used in the specification of thepresent application refers to a group of the above-defined “C₁ to C₂₂alkyl group” having the above-defined “C₃ to C₁₄ cycloalkyl group” as asubstituent. Specific examples include a cyclopropylmethyl group,cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group,cycloheptylmethyl group and cyclooctylmethyl group. For example, acyclopropylmethyl group, cyclobutylmethyl group and cyclopentylmethylgroup are preferable.

The “C₁ to C₂₂ alkoxy group” used in the specification of the presentapplication refers to a group obtained by bonding an oxygen atom to aterminal of the above-defined “C₁ to C₂₂ alkyl group”. Examples of thesuitable group include a methoxy group, ethoxy group, n-propoxy group,iso-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group,tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxygroup, n-hexyloxy group, iso-hexyloxy group, 1,1-dimethylpropyloxygroup, 1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group,1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group,1,2,2-trimethylpropoxy group, 1,1-dimethylbutoxy group,1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutyloxygroup, 1,3-dimethylbutoxy group, 2-ethylbutoxy group, 2-methylpentoxygroup, 3-methylpentoxy group and hexyloxy group. For example, a methoxygroup, ethoxy group, n-propoxy group, iso-propoxy group, iso-butoxygroup and 2,2-dimethylpropyloxy group are preferable.

The “unsaturated C₂ to C₂₂ alkoxy group” used in the specification ofthe present application refers to a group obtained by bonding an oxygenatom to a terminal of the above-defined “unsaturated C₂ to C₂₂ alkylgroup”. Examples of the suitable group include a vinyloxy group,allyloxy group, 1-propenyloxy group, isopropenyloxy group,2-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group, 1-butenyloxygroup, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group,1-hexenyloxy group, 1,3-hexanedienyloxy group, 1,5-hexanedienyloxygroup, propargyloxy group and 2-butynyloxy group. For example, anallyloxy group, propargyloxy group and 2-butynyloxy group arepreferable.

The “C₆ to C₁₄ aryloxy group” used in the specification of the presentapplication refers to a group obtained by bonding an oxygen atom to aterminal of the above-defined “C₆ to C₁₄ aryl group”. Specific examplesinclude a phenyloxy group, indenyloxy group, 1-naphthyloxy group,2-naphthyloxy group, azulenyloxy group, heptalenyloxy group,indacenyloxy group, acenaphthyloxy group, fluorenyloxy group,phenalenyloxy group, phenanthrenyloxy group, and anthracenyloxy group.For example, a phenyloxy group, 1-naphthyloxy group and 2-naphthyloxygroup are preferable.

The “C₇ to C₂₂ aralkyloxy group” used in the specification of thepresent application refers to a group obtained by bonding an oxygen atomto a terminal of the above-defined “C₇ to C₂₂ aralkyl group”. Specificexamples include a benzyloxy group, phenethyloxy group,3-phenylpropyloxy group, 4-phenylbutyloxy group, 1-naphthylmethyloxygroup and 2-naphthylmethyloxy group. For example, a benzyloxy group ispreferable.

The “5-membered to 14-membered heteroaralkyloxy group” used in thespecification of the present application refers to a group obtained bybonding an oxygen atom to a terminal of the above-defined “5-membered to14-membered heteroaralkyl group”. Specific examples include athienylmethyloxy group, furylmethyloxy group, pyridinylmethyloxy group,pyridazinylmethyloxy group, pyrimidinylmethyloxy group andpyrazinylmethyloxy group. For example, a thienylmethyloxy group,furylmethyloxy group and pyridinylmethyloxy group are preferable.

The “5-membered to 14-membered heteroaryloxy group” used in thespecification of the present application refers to a group obtained bybonding an oxygen atom to a terminal of the above-defined “5-membered to14-membered heteroaryl group”. Specific examples include a pyrrolyloxygroup, pyridinyloxy group, pyridazinyloxy group, pyrimidinyloxy group,pyrazinyloxy group, triazolyloxy group, tetrazolyloxy group,benzotriazolyloxy group, pyrazolyloxy group, imidazolyloxy group,benzimidazolyloxy group, indolyloxy group, isoindolyloxy group,indolizinyloxy group, purinyloxy group, indazolyloxy group,quinolinyloxy group, isoquinolinyloxy group, quinolizinyloxy group,phthalazyloxy group, naphthyridinyloxy group, quinoxalinyloxy group,quinazolinyloxy group, cinnolinyloxy group, pteridinyloxy group,imidazotriazinyloxy group, pyrazinopyridazinyloxy group, acridinyloxygroup, phenanthridinyloxy group, carbazolyloxy group, carbazolinyloxygroup, perimidinyloxy group, phenanthrolinyloxy group, phenazinyloxygroup, imidazopyridinyloxy group, imidazopyrimidinyloxy group,pyrazolopyridinyloxy group, pyrazolopyridinyloxy group, thienyloxygroup, benzothienyloxy group, furyloxy group, pyranyloxy group,cyclopentapyranyloxy group, benzofuryloxy group, isobenzofuryloxy group,thiazolyloxy group, isothiazolyloxy group, benzothiazolyloxy group,benzothiadiazolyloxy group, phenothiazinyloxy group, isoxazolyloxygroup, furazanyloxy group, phenoxazinyloxy group, oxazolyloxy group,isoxazolyloxy group, benzoxazolyloxy group, oxadiazolyloxy group,pyrazolooxazolyloxy group, imidazothiazolyloxy group, thienofuranyloxygroup, furopyrrolyloxy group and pyridoxazinyloxy group. For example, athienyloxy group, pyridinyloxy group, pyrimidinyloxy group andpyrazinyloxy group are preferable.

The “aliphatic C₂ to C₂₂ acyl group” used in the specification of thepresent application refers to a group obtained by bonding a carbonylgroup to a terminal of the above-defined “C₁ to C₂₂ alkyl group” or“unsaturated C₂ to C₂₂ alkyl group”. Examples include an acetyl group,propionyl group, butyryl group, iso-butyryl group, valeryl group,iso-valeryl group, pivaloyl group, caproyl group, decanoyl group,lauroyl group, myristoyl group, palmitoyl group, stearoyl group,arachidoyl group, acryloyl group, propiolic group, crotonyl group,iso-crotonyl group, oleinol group and linolenoyl group. An aliphaticacyl group having 2 to 6 carbon atoms, for example, an acetyl group,propionyl group, butyryl group, isobutyryl group and acryloyl group arepreferable.

The “aromatic C₇ to C₁₅ acyl group” used in the specification of thepresent application refers to a group obtained by bonding a carbonylgroup to a terminal of the above-defined “C₆ to C₁₄ aryl group” or“5-membered to 14-membered heteroaryl group”. Examples include a benzoylgroup, 1-naphthoyl group, 2-naphthoyl group, picolinoyl group,nicotinoyl group, isonicotinoyl group, furoyl group andthiophenecarbonyl group. For example, a benzoyl group, picolinoyl group,nicotinoyl group and isonicotinoyl group are preferable.

The “C₁ to C₂₂ alkylsulfonyl group” used in the specification of thepresent application refers to a sulfonyl group to which theabove-defined “C₁ to C₂₂ alkyl group” is bonded. Specific examplesinclude a methylsulfonyl group, ethylsulfonyl group, n-propylsulfonylgroup and iso-propylsulfonyl group. For example, a methylsulfonyl groupis preferable.

The “C₆ to C₁₄ arylsulfonyl group” used in the specification of thepresent application refers to a sulfonyl group to which theabove-defined “C₆ to C₁₄ aryl group” is bonded. Specific examplesinclude a benzenesulfonyl group, 1-naphthalenesulfonyl group and2-naphthalenesulfonyl group. For example, a benzenesulfonyl group ispreferable.

The “aliphatic C₂ to C₂₂ acyloxy group” used in the specification of thepresent application refers to a group obtained by bonding an oxygen atomto a terminal of the above-defined “aliphatic C₂ to C₂₂ acyl group”.Examples include an acetoxy group, propionyloxy group and acryloxygroup. For example, an acetoxy group and propionyloxy group arepreferable.

The “C₂ to C₂₂ alkoxycarbonyl group” used in the specification of thepresent application refers to a group obtained by bonding a carbonylgroup to a terminal of the above-defined “C₁ to C₂₂ alkoxy group”.Examples include a methoxycarbonyl group, ethoxycarbonyl group,n-propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonylgroup, iso-butoxycarbonyl group, sec-butoxycarbonyl group, andtert-butoxycarbonyl group. For example, an ethoxycarbonyl group,iso-propoxycarbonyl group and tert-butoxycarbonyl group are preferable.

The “unsaturated C₃ to C₂₂ alkoxycarbonyl group” used in thespecification of the present application refers to a group obtained bybonding a carbonyl group to a terminal of the above-defined “unsaturatedC₂ to C₂₂ alkoxy group”. Examples include a vinyloxycarbonyl group,allyloxycarbonyl group, 1-propenyloxycarbonyl group,iso-propenyloxycarbonyl group, propargyloxycarbonyl group and2-butynyloxycarbonyl group. For example, an allyloxycarbonyl group ispreferable.

The “C₁ to C₂₂ alkylthio group” used in the specification of the presentapplication refers to a group obtained by bonding a sulfur atom to aterminal of the above-defined “C₁ to C₂₂ alkyl group”. Examples includea methylthio group, ethylthio group, n-propylthio group andiso-propylthio group. For example, a methylthio group and ethylthiogroup are preferable.

The “C₁ to C₂₂ alkylsulfinyl group” used in the specification of thepresent application refers to a group obtained by bonding a sulfinylgroup to a terminal of the above-defined “C₁ to C₂₂ alkyl group”.Examples include a methylsulfinyl group, ethylsulfinyl group,n-propylsulfinyl group and iso-propylsulfinyl group. For example, amethylsulfinyl group and ethylsulfinyl group are preferable.

The “C₁ to C₂₂ alkylsulfonyloxy group” used in the specification of thepresent application refers to a group obtained by bonding an oxygen atomto a terminal of the above-defined “C₁ to C₂₂ alkylsulfonyl group”.Examples include a methanesulfonyloxy group, ethanesulfonyloxy group,n-propanesulfonyloxy group and iso-propanesulfonyloxy group. Forexample, a methylsulfonyloxy group is preferable.

Given as the substituent in a group “which may have a substituent” usedin the specification of the present application is one or more groupsselected from:

-   (1) a halogen atom,-   (2) a hydroxyl group,-   (3) a thiol group,-   (4) a nitro group,-   (5) a nitroso group,-   (6) a cyano group,-   (7) a carboxyl group,-   (8) a hydroxy sulfonyl group,-   (9) an amino group,-   (10) a C₁ to C₂₂ alkyl group    (for example, a methyl group, ethyl group, n-propyl group,    iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group or    tert-butyl group),-   (11) an unsaturated C₂ to C₂₂ alkyl group    (for example, a vinyl group, allyl group, 1-propenyl group,    isopropenyl group, ethynyl group, 1-propynyl group, 2-propynyl    group, 1-butynyl group, 2-butynyl group or 3-butynyl group),-   (12) a C₆ to C₁₄ aryl group    (for example, a phenyl group, 1-naphthyl group or 2-naphthyl group),-   (13) a 5-membered to 14-membered heteroaryl group    (for example, a thienyl group, furyl group, pyridinyl group,    pyridazinyl group, pyrimidinyl group or pyrazinyl group),-   (14) a 3-membered to 14-membered non-aromatic heterocyclic group    (for example, an aziridinyl group, azetidyl group, pyrrolidinyl    group, pyrrolyl group, piperidinyl group, piperazinyl group,    homopiperidinyl group, homopiperazinyl group, imidazolyl group,    pyrazolidinyl group, imidazolidyl group, morpholinyl group,    thiomorpholinyl group, imidazolinyl group, oxazolinyl group or    quinuclidinyl group),-   (15) a C₃ to C₁₄ cycloalkyl group    (for example, a cyclopropyl group, cyclobutyl group, cyclopentyl    group, cyclohexyl group, cycloheptyl group or cyclooctyl group),-   (16) a C₁ to C₂₂ alkoxy group    (for example, a methoxy group, ethoxy group, n-propoxy group,    iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy    group or tert-butoxy group),-   (17) an unsaturated C₂ to C₂₂ alkoxy group    (for example, a vinyloxy group, allyloxy group, 1-propenyloxy group,    isopropenyloxy group, ethynyloxy group, 1-propynyloxy group,    2-propynyloxy group, 1-butynyloxy group or 2-butynyloxy group),-   (18) a C₆ to C₁₄ aryloxy group    (for example, a phenyloxy group, 1-naphthyloxy group or    2-naphthyloxy group),-   (19) a C₇ to C₂₂ aralkyloxy group    (for example, a benzyloxy group, phenethyloxy group,    3-phenylpropyloxy group, 4-phenylbutyloxy group, 1-naphthylmethyloxy    group or 2-naphthylmethyloxy group),-   (20) a 5-membered to 14-membered heteroaralkyloxy group    (for example, a thienylmethyloxy group, furylmethyloxy group,    pyridinylmethyloxy group, pyridazinylmethyloxy group,    pyrimidinylmethyloxy group or pyrazinylmethyloxy group),-   (21) a 5-membered to 14-membered heteroaryloxy group    (for example, a thienyloxy group, furyloxy group, pyridinyloxy    group, pyridazinyloxy group, pyrimidinyloxy group or pyrazinyloxy    group),-   (22) an aliphatic C₂ to C₂₂ acyl group    (for example, an acetyl group, propionyl group, butyryl group,    iso-butyryl group, valeryl group, iso-valeryl group, pivalyl group,    caproyl group, decanoyl group, lauroyl group, myristoyl group,    palmitoyl group, stearoyl group, arachidoyl group, acrylyl group,    propiolic group, crotonyl group, iso-crotonyl group, oleinoyl group    or linolenoyl group),-   (23) an aromatic C₇ to C₁₅ acyl group    (for example, a benzoyl group, 1-naphthoyl group or 2-naphthoyl    group),-   (24) an aliphatic C₂ to C₂₂ acyloxy group    (for example, an acetoxy group, propionyloxy group or acryloxy    group),-   (25) a C₂ to C₂₂ alkoxycarbonyl group    (for example, a methoxycarbonyl group, ethoxycarbonyl group,    n-propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonyl    group, iso-butoxycarbonyl group, sec-butoxycarbonyl group or    tert-butoxycarbonyl group),-   (26) an unsaturated C₃ to C₂₂ alkoxycarbonyl group    (for example, a vinyloxycarbonyl group, allyloxycarbonyl group,    1-propenyloxycarbonyl group, isopropenyloxycarbonyl group,    propargyloxycarbonyl group or 2-butynyloxycarbonyl group),-   (27) a C₁ to C₂₂ alkylthio group    (for example, a methylthio group, ethylthio group, n-propylthio    group or iso-propylthio group),-   (28) a C₁ to C₂₂ alkylsulfinyl group    (for example, a methylsulfinyl group, ethylsulfinyl group,    n-propylsulfinyl group or iso-propylsulfinyl group),-   (29) a C₁ to C₂₂ alkylsulfonyl group    (for example, a methylsulfonyl group, ethylsulfonyl group,    n-propylsulfonyl group or iso-propylsulfonyl group),-   (30) a C₆ to C₁₄ arylsulfonyl group    (for example, a benzenesulfonyl group, 1-naphthalenesulfonyl group    or 2-naphthalenesulfonyl group),-   (31) a C₁ to C₂₂ alkylsulfonyloxy group    (for example, a methylsulfonyloxy group, ethylsulfonyloxy group,    n-propylsulfonyloxy group or iso-propylsulfonyloxy group),-   (32) a carbamoyl group,-   (33) a formyl group, and the like. For example, an amino group, a C₁    to C₂₂ alkyl group, an unsaturated C₂ to C₂₂ alkyl group, a C₆ to    C₁₄ aryl group, a 5-membered to 14-membered heteroaryl group, a    3-membered to 14-membered non-aromatic heterocyclic group and a C₃    to C₁₄ cycloalkyl group are preferable. In particular, the    substituent is preferably one or two substituents such as an amino    group, a C₁ to C₂₂ alkyl group, a 3-membered to 14-membered    non-aromatic heterocyclic group, and a C₃ to C₁₄ cycloalkyl group,    for example. In addition, the above-described amino group (9) and    carbamoyl group (31) given as the substituents in the    above-described group “which may have a substituent” may be each    further substituted with one or two C₁ to C₂₂ alkyl groups,    unsaturated C₂ to C₂₂ alkyl groups or C₆ to C₁₄ aryl groups.

Next, the compound of the formula (I) of the present invention will beelucidated.

The compound of the formula (I) inhibits VEGF production under a hypoxiccondition, possesses an activity of inhibiting proliferation of solidcancer cells in vivo, and shows in vivo activity at a dose not causing asignificant reduction in the body weight. Among them, theabove-described compound of the formula (I-a) is preferable, and thecompound of the formula (I-b) is more preferable, and the compound ofthe formula (I-c) is particularly preferable. Further, the compound ofthe formula (I), wherein R¹⁶ is a hydroxyl group, is a compoundexhibiting particularly excellent stability in an aqueous solution.

Since the compound of the formula (I) is prepared by using a knownconversion reaction for functional groups (for example, a hydroxylgroup) present at the 3-position, 7-position, 16-position and21-position, the same substituents can be introduced into the3-position, 7-position, 16-position and 21-position. Since thestructural feature is the side chain at the 7-position and/or the sidechain at the 21-position, a group of more preferable compounds can bedefined as the compounds of the formula (I-d). In addition, thecompounds of the formula (I), wherein R²¹ forms an oxo moiety togetherwith a carbon atom to which R²¹ is bonded, as well as the compounds ofthe formula (I-d), represent a group of compounds possessing goodactivity. As detailed aspects of more preferable compounds among thecompounds of the formula (I-d), the compounds of the above-describeditems “7.” to “20.” of the present invention can be exemplified.

Preferable examples of the compound of the formula (I) will be describedbelow. A group of preferable compounds, including compounds oflater-described examples, is represented by, for example,

-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 18),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 19),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1-yl(carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 21),-   (8E,12E,14E)-7-((4-ethylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 24),    (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(3-(N′,N′-dimethylamino)propyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 27),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 28),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 29),    (8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 39),-   (8E,12E,14E)-3,16,21-trihydroxy-7-((4-(4-hydroxypiperidin-1-yl)piperidin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 40),-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(morpholin-4-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    compound 42),-   (8E,12E,14E)-7-((4-ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 43),    (8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 44),-   (8E,12E,14E)-3,16,21-trihydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 49),-   (8E,12E,14E)-7-(N-(2-(N′,N′-dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 50),-   (8E,12E,14E)-7-(N-(2-(N′,N′-dimethylamino)ethyl)carbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 51) or-   (8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide    (compound 55). Of these, for example, compound 29, compound 39,    compound 43, compound 44 and compound 55 are more preferable.

Next, a method for producing the compound of the formula (I) of thepresent invention will be described.

The compound of the formula (I) can be produced by chemical modificationof, a key compound such as a 6-deoxy 11107 compound or a 6-deoxycompound using a conventional method as follows. The 6-deoxy 11107compound is obtained by culturing, under aerobic conditions, a strainbelonging to the genus Streptomyces, which is capable of producing a6-deoxy 11107 compound as a physiologically active substance of theformula (I), wherein [1] W is

-   R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶,    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom (6-deoxy 11107B),-   [3] W is-   R³, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom (6-deoxy 11107D),-   [7] W is-   R³, R¹⁷, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group,    and R²⁰ and R^(21′) are a hydrogen atom, and collecting the compound    from the cells and culture solution; and the 6-deoxy compound is    obtained by biologically converting a compound of the formula (I),    wherein-   [1] W is-   R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶,    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom (hereinafter referred to as    “6-deoxy 11107B”) to a compound of the formula (I), wherein-   [2] W is-   R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶,    R¹⁷, R²⁰ and R^(21′) are a hydrogen atom,-   [4] W is-   R²¹ and R^(21′) form an oxo group together with carbon to which R²¹    and R^(21′) are bonded, R³, R¹⁶ and R²⁰ are a hydroxyl group, R⁷ is    an acetoxy group, and R¹⁷ is a hydrogen atom,-   [5] W is-   R³, R¹⁶, R²⁰ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group,    and R¹⁷ and R^(21′) are a hydrogen atom,-   [6] W is-   R³, R⁷, R¹⁶ and R²¹ are a hydroxyl group, and R¹⁷, R²⁰ and R^(21′)    are a hydrogen atom or-   [8] W is-   R²¹ and R^(21′) form an oxo group together with carbon to which R²¹    and R^(21′) are bonded, R³ and R¹⁶ are a hydroxyl group, R⁷ is an    acetoxy group, and R¹⁷ and R²⁰ are a hydrogen atom; and by    chemically modifying the key compound using a conventional method in    an appropriate manner.

The present invention will be described in detail below with respect tothe production of the 6-deoxy 11107 compound by fermentation, theproduction of the 6-deoxy compound by bioconversion reaction, and themodification of the active substance by organic synthesis.

First, a method for producing the 6-deoxy 11107 compound will bedescribed.

The 6-deoxy 11107 compound (in particular, 6-deoxy 11107B) that can beconverted into the 6-deoxy 11107D compound, a biologically activesubstance, of the present invention can be produced by microorganismfermentation.

As a microorganism used for producing the 6-deoxy 11107 compound, anymicroorganism can be used insofar as the microorganism is a strain whichis capable of producing the 6-deoxy 11107 compound. For example, astrain for producing 6-deoxy 11107B can be obtained from a strainisolated from soil or a known strain which is capable of producing a11107B analogue, by typical mutation treatment using ultraviolet rays ora mutagenic agent such as N-methyl-N′-nitro-N-nitrosoguanidine (NTG) asa mutagen, for example, or by a method such as gene disruption byhomologous recombination.

As a microorganism used for producing the 6-deoxy 11107 compound, thefollowing deposited strain can be exemplified. The above-describedstrain is internationally deposited with International Patent OrganismDepositary (IPOD), National Institute of Advanced Industrial Science andTechnology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566,Japan. Specifically, Streptomyces sp. Mer-11107 was deposited withNational Institute of Bioscience and Human-Technology, Agency ofIndustrial Science and Technology in 1-1-3 Higashi, Tsukuba-shi, Ibaraki305-8566, Japan as FERM P-18144 on Dec. 19, 2000, and was transferred toInternational Patent Organism Depositary (IPOD), National Institute ofAdvanced-Industrial Science and Technology in Central 6, 1-1-1 Higashi,Tsukuba-shi, Ibaraki 305-8566, Japan under the international depositarynumber FERM BP-7812 on Nov. 27, 2001.

There are no specific limitations to the strains for producing the6-deoxy 11107 compound, including mutants of these strains, insofar asthey belong to the genus Streptomyces, and are capable of producing the6-deoxy 11107 compound. In addition to the above-described strain,Streptomyces sp. A-1543 can be exemplified, for example. This strain wasdeposited with International Patent Organism Depositary, NationalInstitute of Advanced Industrial Science and Technology in Central 6,1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan as FERM P-18942 onJul. 23, 2002, and was transferred to International Patent OrganismDepositary (IPOD), National Institute of Advanced Industrial Science andTechnology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566,Japan under the international depositary number FERM BP-8442 on Jul. 28,2003.

Next, the production of the 6-deoxy 11107 compound will be described indetail with respect to 1. characteristics of the isolated productionstrain, 2. a method for culturing the production strain, and 3. a methodfor purifying the active substance.

1. Characteristics of the Isolated Production Strain

It is expected that, as a strain used in the present invention, anystrain belonging to the genus Streptomyces which is capable of producingthe 6-deoxy 11107 compound can be used. As representative strains, astrain numbered as Mer-11107 by the present inventors and A-1543 as amutant of this strain can be given. Microbiological characteristics ofthese strains are as follows.

(1). Morphology

In the strain, spiral aerial hyphae are elongated from substrate hyphae.At the end of the matured aerial hyphae, a spore chain composed of about10 to 20 cylindrical spores is formed. Each spore has a size of about0.7 μm×1.0 μm, and has a smooth surface. No atypical organs such assporangia, sclerotia, and flagella are observed.

(2). Growth Conditions in Various Culture Media

Culture characteristics of the strain after culturing on various culturemedia at 28° C. for two weeks are shown as follows. Color tones aredescribed according to the Tresner's color wheels, and indicated as acolor name and a symbol shown in parentheses.

1) Yeast-Extract Malt Extract Agar

The strain grows well. On the surface, aerial hyphae of the culturedstrain are branched, become divided and form gray spores (light gray;d). The reverse side color is light melon yellow (3ea). No solublepigment is observed.

2) Oatmeal Agar

The strain grows moderately. On the surface, the aerial hyphae of thecultured strain are slightly branched, become divided to form grayspores (gray; g). The reverse side color is Nude tan (4gc) or putty (1½ec). No soluble pigment is observed.

3) Inorganic Salts-Starch Agar

The strain grows well. On the surface, aerial hyphae adhere of thecultured strain are branched, become divided and form gray spores (gray;e). The reverse side color is fawn (4ig) or gray (g). No soluble pigmentproduction is observed.

4) Glycerol-Asparagine Agar

The strain grows well. On the surface, aerial hyphae of the culturedstrain are branched, become divided and form white spores (white; a).The reverse side color is pearl pink (3ca). No soluble pigment isobserved.

5) Peptone-Yeast Extract-Iron Agar

The strain grows poorly. On the surface, no aerial hyphae of thecultured strain are branched. The reverse side color is light melonyellow (3ea). No soluble pigment is observed.

6) Tyrosine Agar

The strain grows well. On the surface, aerial hyphae adhere of thecultured strain are branched, become divided and form white spores(white; a). The reverse side color is pearl pink (3ca). No solublepigment is observed.

(3). Various Carbon Sources Utilization

Growth conditions of the strain after culturing in a medium, in whichvarious carbon sources are added to a Pridham-Godlieb agar culturemedium, at 28° C. for two weeks are shown as follows.

1) L-arabinose ±

2) D-xylose ±

3) D-glucose +

4) D-fructose +

5) Sucrose +

6) Inositol +

7) L-rhamnose −

8) D-mannitol +

9) Raffinose +

(The symbol “+” means “positive”, the symbol “±” means “weaklypositive”, and the symbol “−” means “negative”).

(4). Physiological Properties

Physiological properties of the strain are as follows.

(a) Temperature range for growth (yeast-malt extract agar, cultured fortwo weeks): 12° C. to 37° C.

(b) Optimal temperature range for growth (yeast extract-malt extractagar, cultured for two weeks): 21° C. to 33° C.

(c) Gelatin liquefaction (glucose-peptone-gelatin medium): negative

(d) Milk coagulation (skim milk medium): negative

(e) Milk peptonization (skim milk medium): negative

(f) Starch hydrolysis (Inorganic salt-starch): positive

(g) Formation of melanoid pigment (peptone-yeast extract-iron agar):negative (tyrosine agar): negative

(h) Hydrogen sulfide production (peptone-yeast extract-iron agar):negative

(i) Nitrate reduction (0.1% potassium nitrate-containing broth):negative

(j) NaCl tolerance (yeast extract-malt extract agar, cultured for twoweeks):

Growing at NaCl concentration of 4% or less

(5). Cell Component

LL-diaminopimelic acid was detected from the cell walls of the strain.

2. A Method for Culturing the Production Strain

The 6-deoxy 11107 compound of the present invention can be produced byinoculating the above-described strain into a nutrient culture medium,and aerobically culturing the strain. As a strain for producing the6-deoxy 11107 compound, any strain belonging to the genus Streptomyceswhich is capable of producing the 6-deoxy 11107 compound can be used inthe present invention without limitations to the above-described strain.

Although the method for culturing the above-described microorganism is,in principle, in accordance with a method for culturing a commonmicroorganism, it is usually preferable that the method be conductedunder aerobic conditions as shaking flask culture, tank culture, or thelike by liquid culture. Any culture medium may be used for the culture,insofar as the medium contains a nutrient source that can be utilized bya microorganism belonging to the genus Streptomyces. Any of varioussynthetic culture media semi-synthetic culture media and natural culturemedia can be used. In the culture medium composition, as carbon sources,glucose, sucrose, fructose, glycerol, dextrin, starch, molasses andsoybean oil, for example, can be used singly or in a combination of twoor more. As nitrogen sources, organic nitrogen sources such aspharmamedia, peptone, meat extract, soybean meal, casein, amino acid,yeast extract and urea, for example, and inorganic nitrogen sources suchas sodium nitrate and ammonium sulfate, for example, can be used singlyor in a combination of two or more. In addition, for example, salts suchas sodium chloride, potassium chloride, calcium carbonate, magnesiumsulfate, sodium phosphate, potassium phosphate, and cobalt chloride,heavy metal salts, and vitamins such as vitamin B and biotin can beadded for use as required. In the case where a culture medium is foamedwhen culturing, various antifoaming agents can be appropriately added tothe culture medium. When the antifoaming agent is added, theconcentration must be adjusted so that production of the targetsubstance is not adversely affected. For example, the concentration usedis preferably 0.05% or less.

The culture conditions can be appropriately selected, insofar as theabove-described strain is grown well so that the above-describedsubstance can be produced. It is preferable that the pH of a culturemedium be adjusted to about 5 to 9, for example, and typically nearneutral. It is appropriate that the culture temperature be maintained attypically 20 to 40° C., and preferably 23 to 35° C. The culture periodis about two to eight days, and typically about three to five days. As amatter of course, various culture conditions as described above can bechanged according to the species and properties of the microorganismused, external conditions, and the like, and optimal conditions can beselected. The 6-deoxy 11107 compound of the present inventionaccumulated in a culture solution can be collected by a typicalseparation methods utilizing its characteristics, for example, solventextraction or resin adsorption.

3. A Method for Purifying the Active Substance

After termination of the culture, in order to collect the 6-deoxy 11107compound from a culture solution, separation and purification methodsused for isolating a microbial metabolite from the culture solution canbe generally used. For example, all known methods such as organicsolvent extraction using methanol, ethanol, butanol, ethyl acetate,chloroform, or the like, various types of ion exchange chromatography,gel filtration chromatography using Sephadex LH-20 or the like, activecarbon, adsorption-desorption treatment by adsorption chromatography orthin-layer chromatography using silica gel or the like, andhigh-performance liquid chromatography using a reverse phase column areapplicable to this method. The purification method is not specificallylimited to the methods listed here.

By using these methods singly, in a combination of two or more in anarbitrary order, or repetitively, the 6-deoxy 11107 compound can beisolated and purified.

Second, a method for producing the 6-deoxy 11107 compound will bedescribed.

1. A Microorganism Which Produces the 6-Deoxy Compound by Bioconversion

The 6-deoxy compound of the present invention can be obtained byhydroxylation of the hydrogen atom at the 16-position of the 6-deoxy11107 compound obtained in the above-described method (in particular,6-deoxy 11107B) by bioconversion.

As a microorganism used for producing the 6-deoxy 11107 compound, anymicroorganism can be used insofar as the microorganism is a straincapable of hydroxylating the hydrogen atom at the 16-position of the6-deoxy 11107 compound (in particular, 6-deoxy 11107B) to convert thecompound into the 6-deoxy 11107D compound of the present invention. Asrepresentative examples of such a microorganism, strain A-1544 andstrain A-1545 separated from the soil by the present inventors can begiven. These strains were deposited with International Patent OrganismDepositary, National Institute of Advanced Industrial Science andTechnology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566,Japan as FERM P-18943 and FERM P-18944, respectively, on Jul. 23, 2002,and were transferred to International Patent Organism Depositary (IPOD),National Institute of Advanced Industrial Science and Technology inCentral 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan under theinternational depositary numbers FERM BP-8446 and FERM BP-8447,respectively, on Jul. 30, 2003.

2. Production of the 6-Deoxy Compound by Bioconversion Reaction

The 6-deoxy compound is produced by causing the 6-deoxy 11107 compound(in particular, 6-deoxy 11107B) to come in contact with cells or a cellpreparation of the above-described strain or its mutant. Typically, the6-deoxy compound is produced by adding the 6-deoxy 11107 compound (inparticular, 6-deoxy 11107B) as a precursor compound to a culturesolution obtained by inoculating the above-described strain into anutrient source-containing culture medium and aerobically culturing thestrain, or to a suspension of washed cells of the above-described strainin an appropriate buffer solution. When the compound is produced in aculture solution, the 6-deoxy 11107 compound (in particular, 6-deoxy11107B) may be added to the culture solution in any time before theculture or in a prescribed period of time after initiation of theculture. Although such a strain for preparing a culture solution orwashed cells can be cultured, or such a strain with the precursorcompound added can be cultured, typically according to a method forculturing a common microorganism, it is usually preferable that theculture be conducted under aerobic conditions as shaking flask cultureor tank culture by liquid culture, or the like.

Any culture medium may be used for the culture, insofar as the mediumcontains a nutrient source that can be utilized by a microorganism. Anyof various synthetic culture media, semi-synthetic culture media andnatural culture media can be used.

In the culture medium composition, as carbon sources, glucose,galactose, sucrose, maltose, fructose, glycerin, dextrin, starch,molasses and soybean oil, for example, can be used singly or in acombination of two or more. As nitrogen sources, organic nitrogensources such as pharmamedia, peptone, meat extract, soybean meal, fishmeal, gluten meal, casein, dry yeast, amino acid, yeast extract andurea, for example, and inorganic nitrogen sources such as sodium nitrateand ammonium sulfate, for example, can be used singly or in acombination of two or more. In addition, for example, salts such assodium chloride, potassium chloride, calcium carbonate, magnesiumsulfate, sodium phosphate, potassium phosphate, copper sulfate, ironsulfate, manganese chloride, and cobalt chloride, heavy metal salts,vitamins such as vitamin B and biotin, and clathrating agent such ascyclodextrins can be added for use as required. In the case where aculture medium is foamed when culturing, various antifoaming agents canbe appropriately added to the culture medium. When the antifoaming agentis added, the concentration must be adjusted so that production of thetarget substance is not adversely affected.

The culture conditions can be appropriately selected, insofar as theabove-described strain is grown well so that the 6-deoxy 11107 compound(in particular, 6-deoxy 11107B) can.be converted to produce the 6-deoxycompound. It is preferable that the pH of a culture medium be adjustedto 5 to 9, for example, and typically near the neutrality. It isappropriate that the culture temperature be maintained at typically 20to 40° C., and preferably 24 to 30° C. The culture days are one to eightdays, and typically two to five days.

As a matter of course, various culture conditions as described above canbe adjusted according to the species and properties of the microorganismused, external conditions, and the like, and optimal conditions can beselected. The 6-deoxy compound accumulated in a culture solution can berecovered by a typical separation methods utilizing its characteristics,for example, solvent extraction or resin adsorption.

3. A Method for Purifying the 6-Deoxy Compound

After termination of the culture, in order to collect the 6-deoxycompound from a culture solution, separation and purification methodsused for isolating a microbial metabolite from the culture solution canbe generally employed, according to the method of purifying the 6-deoxy11107 compound (in particular, 6-deoxy 11107B) as described above. Byusing these methods singly, in a combination of two or more in anarbitrary order, or repetitively, the 6-deoxy compound can be isolatedand purified.

Next, a method for preparing the compound of the formula (I) other thanthe 6-deoxy 11107 compound and the 6-deoxy compound will be described.

Various compounds of the formula (I) can be synthesized by converting ahydroxyl group and/or an acetoxy group on the isolated and purified6-deoxy 11107 or 6-deoxy compound as a starting compound using a generalorganic synthetic procedures. Typical examples of the synthetic methodinclude A. a method for preparing an urethane derivative, B. a methodfor preparing a thiourethane derivative, C. a method for preparing anether derivative, D. a method for preparing an ester derivative, E. amethod for preparing a phosphoric ester derivative or amidophosphoricester derivative, F. a method for preparing a sulfuric ester derivativeor amidosulfuric ester derivative, G. a method for preparing a halogenderivative, H. a method for preparing a sulfonic ester derivative, I. amethod for preparing an amine derivative and J. a method for preparingan oxo derivative by oxidation of a hydroxyl group. Introduction andremoval of a protective group for a hydroxyl group, while depending onthe type of the productive group and the stability of the compound usedfor the preparation, can be conducted according to beed by the methoddescribed in document (see T. W. Green, Protective Groups in OrganicSynthesis, John Wiley & Sons Inc., 3rd Edition) or a method similar tothis method. The compound of the formula (I) can be prepared by usingthe introduction or removal reactions of the protective group for ahydroxyl group and the above-described preparation in a suitablecombination. Specifically, the compound of the formula (I), wherein R³,R⁷, R¹⁶, R¹⁷, R²⁰ and R²¹ are substituents as listed in theabove-described category 10), can be prepared using the preparation foran urethane derivative, a thiourethane derivative, an amidosulfuricester derivative and an amine derivative, or the like; the compound ofthe formula (I), wherein R³, R⁷, R¹⁶, R¹⁷, R²⁰ and R²¹ are substituentsas listed in the above-described categories 3) to 6), can be preparedusing the perparation for an ether derivative; the compound of theformula (I), wherein R³, R⁷, R⁶, R¹⁷, R²⁰ and R²¹ are substituents aslisted in the above-described category 7), can be prepared using thepreparation for an ester derivative; the compound of the formula (I),wherein R³, R⁷, R¹⁶, R¹⁷, R²⁰ and R²¹ are substituents as listed in theabove-described category 12) or 13), can be prepared using thepreparation for a phosphoric ester derivative or the preparation for anamidophosphoric ester derivative; the compound of the formula (I),wherein R³, R⁷, R¹⁶, R¹⁷, R²⁰ and R²¹ are substituents as listed in theabove-described category 11), can be prepared using the preparation fora sulfuric ester derivative or the preparation for a sulfonic esterderivative; the compound of the formula (I), wherein R³, R⁷, R¹⁶, R¹⁷,R²⁰ and R²¹ are substituents as listed in the above-described category9), can be prepared using the preparation for a halogen derivative; thecompound of the formula (I), wherein R³, R⁷, R¹⁶, R¹⁷, R²⁰ and R²¹ aresubstituents as listed in the above-described category 8), can beprepared using an introduction and removal reactions of a protectivegroup for a hydroxyl group; and an oxo derivative of the compound of theformula (I) in the above-described category 1) can be prepared by usingthe preparation for an oxo derivative by oxidation of a hydroxyl group.

Next, various synthetic methods used for preparing the compounds of theformula (I) will be described.A. A Method for Preparing an Urethane Derivative

In the formulas, R^(3x), R^(16x) and R^(21x) independently represent ahydrogen atom or a protective group, provided that R^(3x), R^(16x) andR^(21x) do not concurrently represent a hydrogen atom; R^(3y), R^(16y)and R^(21y) independently represent a hydrogen atom, a protective groupor a group represented by the formula R^(f)O—CO—, wherein R^(f)represents a C₆ to C₁₄ aryl group which may have (a) substituent(s),provided that R^(3y), R^(16y) and R^(21y) do not concurrently representa hydrogen atom; and R^(3c), R^(16c) and R^(21c) independently representa hydrogen atom, a protective group or a group represented by theformula R^(N1)R^(N2)N—CO—, wherein R^(N1) and R^(N2) are the same asdefined above, provided that R^(3c), R^(16c) and R^(21c) do notconcurrently represent a hydrogen atom.

The step A1 is a step of preparing the compound of the formula (IA).This step is carried out by protecting the hydroxyl group(s) of 6-deoxy11107D (the above-described compound as defined in [3]).

The reaction for protecting the hydroxyl group(s), which variesdepending on the type of the protective group, is carried out by aprocedure well known in the synthetic organic chemistry.

Examples of the protective group include 1-ethoxyethyl,tetrahydropyranyl, 1-methyl-1-methoxyethyl, 1-(2-chloroethoxy)ethyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl,4-methoxytetrahydrothiopyranyl-S,S-dioxide, methoxymethyl,methylthiomethyl, methoxyethoxymethyl, trichloroethoxymethyl,trimethylsilylethyl, trimethylsilylethoxymethyl,tert-butyldimethylsilyl, triethylsilyl, diethylisopropylsilyl,trimethylsilyl, triisopropylsilyl, methyl-di-tert-butylsilyl,diphenylmethylsilyl, benzyl, p-methoxybenzyl, p-methylbenzyl,p-nitrobenzyl, p-chlorobenzyl and triphenylmethyl. All or part ofhydroxyl groups can be appropriately protected by these protectivegroups.

For example, each derivative in which a hydroxyl group is protected by1-ethoxyethyl, tetrahydropyranyl, 1-methoxycyclohexyl,4-methoxytetrahydropyranyl 4-methoxytetrahydrothiopyranyl or4-methoxytetrahydrothiopyranyl-S,S-dioxide can be synthesized bytreating 6-deoxy 11107D with a corresponding vinyl ether such as ethylvinyl ether or dihydropyran in the presence of an acid. As the acid,general organic acids such as pyridinium p-toluenesulfonate (PPTS),p-toluenesulfonic acid, camphorsulfonic acid, acetic acid,trifluoroacetic acid or methanesulfonic acid, for example, and generalinorganic acids such as hydrogen chloride, nitric acid, hydrochloricacid and sulfuric acid, for example are used. Preferably, for example,pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid andcamphorsulfonic acid are used. Although there are no specificlimitations to the solvent used for the reaction, an inert solvent whichcan not easily react with a starting material is desirable. Examples ofsuch solvents include ethers such as tetrahydrofuran, diethyl ether,diiso-propyl ether, dioxane and dimethoxyethane; halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachlorideand 1,2-dichloroethane; hydrocarbons such as hexane, benzene andtoluene; ketones such as acetone and methyl ethyl ketone; nitriles suchas acetonitrile; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyridone and hexamethylphosphoramide;and sulfoxides such as dimethyl sulfoxide. Preferably, for example,dichloromethane, chloroform and tetrahydrofuran are used. The reactiontime is 10 minutes to five days, and preferably one to two days. Thereaction temperature is −78° C. to a reflux temperature, and preferablyroom temperature. The amounts of vinyl ether and the acid used for thereaction are 1 to 200 equivalents and 0.05 to 2 equivalents,respectively, and preferably 30 to 50 equivalents and 0.1 to 0.3equivalent, respectively, to 6-deoxy 11107D.

Examples of other protective groups include methoxymethyl,methylthiomethyl, methoxyethoxymethyl, trichloroethoxymethyl,trimethylsilylethyl, trimethylsilylethoxymethyl,tert-butyldimethylsilyl, triethylsilyl, trimethylsilyl,diethylisopropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl,diphenylmethylsilyl, benzyl, p-methoxybenzyl, p-methylbenzyl,p-nitrobenzyl, p-chlorobenzyl and triphenyl methyl. A derivative inwhich the hydroxyl group is protected by these protective groups can besynthesized by reacting a starting material with a chloride, bromide ortrifluoromethanesulfonate of the respective protective group in thepresence of a base. As the base, a general organic base or inorganicbase is used. Examples of the organic base include aromatic bases suchas imidazole, 4-(N,N-dimethylamino)pyridine (which is synonymous with4-dimethylaminopyridine, N,N-dimethylaminopyridine anddimethylaminopyridine used in this specification), pyridine,2,6-lutidine and collidine; tertiary amines such as N-methylpiperidine,N-methylpyrrolidine, triethylamine, trimethylamine,diisopropylethylamine, cyclohexyldimethylamine, N-methylmorpholine and1,8-bis(dimethylamino)naphthalene; secondary amines such asdiisobutylamine and dicyclohexylamine; alkyl lithium such as methyllithium and butyl lithium; and metal alkoxides such as sodium methoxideand sodium ethoxide. Examples of the inorganic base include alkali metalhydrides such as sodium hydride and potassium hydride; alkaline earthmetal hydrides such as calcium hydride; alkali metal hydroxides such assodium hydroxide and potassium hydroxide; alkali metal carbonates suchas sodium carbonate, potassium carbonate and cesium carbonate; andalkali metal hydrogencarbonates such as sodium hydrogen carbonate. Asexamples of the preferable base used for protecting the hydroxyl groupwith a silyl protective group are aromatic bases such as imidazole,4-dimethylaminopyridine and tertiary amines such as triethylamine.Although there are no specific limitations to the solvent used for thereaction, a solvent which can not easily react with the startingmaterial is desirable. Examples of such solvents are the above-describedinert solvents, of which preferred examples are tetrahydrofuran,dichloromethane and N,N-dimethylformamide. The reaction time is 10minutes to three days, and preferably one to two days. The reactiontemperature is −78° C. to a reflux temperature, and preferably −10° C.to 50° C. The amounts of the chloride, bromide ortrifluoromethanesulfonate and the base used for the reaction are 1 to 20equivalents and 0.5 to 30 equivalents, respectively, and preferably 1 to15 equivalents and 0.5 to 20 equivalents, respectively, to 6-deoxy11107D.

The hydroxyl group(s) of 6-deoxy 11107D can be selectively protected byselecting the reagent used for protecting the hydroxyl group(s) and theequivalence thereof. For Example, a compound in which the hydroxylgroups at the 3-position and the 21-position are selectively protectedcan be obtained by carrying out the reaction at room temperature usingchlorotriethylsilane, triethylamine and 4-dimethylaminopyridine indichloromethane, or tert-butylchlorodimethylsilane and imidazole inN,N-dimethylformamide. In this procedure, for example, the hydroxylgroup at the 3-position can be preferentially protected by limiting theequivalence of chlorotriethylsilane or tert-butylchlorodimethylsilane.Further, after protecting two or three of the four hydroxyl groups bysilyl groups, the remaining two or one hydroxyl groups can be protectedby the above-described ethoxyethyl groups or the like.

The step A2 is a step of preparing the compound of the formula (IIA).This step is carried out by converting the acetoxy group of the compoundof the formula (IA) into the hydroxyl group by treating a base in aninert solvent.

Examples of the base are inorganic bases including alkali metal hydridessuch as sodium hydride and potassium hydride; alkaline earth metalhydrides such as calcium hydride; alkali metal hydroxides such aslithium hydroxide, sodium hydroxide and potassium hydroxide; alkalimetal carbonates such as lithium carbonate, sodium carbonate andpotassium carbonate; alkali metal hydrogen carbonates such as sodiumhydrogen carbonate; and metal alkoxides such as lithium methoxide,sodium methoxide, sodium ethoxide and potassium tert-butoxide, as wellas bases such as guanidine and ammonia. Preferable examples of the baseare potassium carbonate and guanidine.

Examples of the inert solvent used herein include, in addition to theabove-described inert solvents, alcoholic solvents such as methanol,ethanol, isopropanol and tert-butanol, and water. These solvents can beused in a mixture of two or more. Preferable example of the solvent isalcoholic solvent, or a mixture of an alcohol and a halogen solvent. Thereaction time is 10 minutes to five days, and preferably 30 minutesto.one day. The reaction temperature is −78° C. to a reflux temperature,and preferably room temperature. The amount of the base used for thereaction is 1 to 10 equivalents, and preferably 2 to 5 equivalents, tothe compound of the formula (IA).

The step A3 is a step of preparing the compound of the formula (IIIA).This step is carried out by treating the hydroxyl group of the compoundof the formula (IIA) with a chloroformate derivative orcarbonyldiimidazole in the presence of a base. Examples of thechloroformate derivative include 4-nitrophenyl chloroformate, phenylchloroformate, 4-chlorophenyl chloroformate, 4-bromophenyl chloroformateand 2,4-dinitrophenyl chloroformate. Examples of the base include theabove-described organic bases and inorganic bases. Preferably, forexample, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine,pyridine, 2,6-lutidine and sodium hydride are used. Although there areno specific limitations to the solvent used for the reaction, a solventthat does not easily react with the starting material is desirable.Examples of such solvents are the above-described inert solvents, ofwhich, for example, tetrahydrofuran, dichloromethane andN,N-dimethylformamide are preferably used. The amounts of thechloroformate derivative and the base used for the reaction are 1 to 10equivalents and 1 to 20 equivalents, respectively, and preferably 1 to 5equivalents and 1 to 10 equivalents, respectively, to the compound ofthe formula (IIA). The reaction time is 10 minutes to 30 hours, andpreferably one to four hours. The reaction temperature is −78° C. to areflux temperature, and preferably −10° C. to 50° C.

With regard to the hydroxyl compound of the formula (IA), in which oneto three of OR^(3A), OR^(6A), OR^(16A) and OR^(21A) are not protected inthe step A1, the hydroxyl group can be converted into a carbonate groupby the step A3. Specifically, by treating the compound with a base and achloroformate derivative in equivalents corresponding to the number ofhydroxyl groups to be converted into carbonate groups, the hydroxylgroups other than the hydroxyl group at the 7-position of the compound(IA) can be converted into carbonate groups, as in the case of thehydroxyl group at the 7-position.

The step A4 is a step of preparing the compound of the formula (IVA).This step is carried out by treating the carbonate in the compound ofthe formula (IIIA) with an amine (R^(N1)R^(N2)H) that can form a desiredcompound of the formula (I) in an inert solvent in the presence of abase, or with the amine alone.

Examples of the amine used herein include methylamine, ethylamine,propylamine, butylamine, octylamine, decylamine, cyclopropylamine,cyclopentylamine, cyclohexylamine, dimethylamine, diethylamine,ethylmethylamine, ethylenediamine, 1,3-propanediamine,1,4-butanediamine, N,N-dimethylethylenediamine,N,N-dimethyl-1,3-propanediamine, N,N-dimethyl-1,4-butanediamine,N,N-diethylethylenediamine, N,N-diethyl-1,3-propanediamine,N,N-diethyl-1,4-butanediamine, N,N,N′-trimethylethylenediamine,N,N,N′-trimethyl-1,3-propanediamine, N,N,N′-trimethyl-1,4-butanediamine,N-ethyl-N′,N′-dimethylethylenediamine,N-ethyl-N′,N′-dimethyl-1,3-propanediamine,N-ethyl-N′,N′-dimethyl-1,4-butanediamine,N,N,N′-triethylethylenediamine, N,N,N′-triethyl-1,3-propanediamine,N,N,N′-triethyl-1,4-butanediamine, N,N-diethyl-N′-methylethylenediamine,N,N-diethyl-N′-methyl-1,3-propanediamine,N,N-diethyl-N′-methyl-1,4-butanediamine,N,N′-dimethyl-N-phenylethylenediamine,N,N′-dimethyl-N-phenyl-1,3-propanediamine,N-benzyl-N,N′-dimethylethylenediamine,N-benzyl-N,N′-dimethyl-1,3-propanediamine, morpholine, thiomorpholine,thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, pyrrolidine,piperidine, piperazine, homopiperazine, 4-hydroxypiperidine,4-methoxypiperidine, 1-methylpiperazine, 1-ethylpiperazine,1-propylpiperazine, 1-butylpiperazine, 1-isopropylpiperazine,1-cyclobutylpiperazine, 1-cyclopentylpiperazine, 1-cyclohexylpiperazine,1-cycloheptylpiperazine, 1-cyclooctylpiperazine,1-(cyclopropylmethyl)piperazine, 1-benzylpiperazine,1-methylhomopiperazine, 1-ethylhomopiperazine,1-(2-aminoethyl)pyrrolidine, 1-(2-(N-methylamino)ethyl)pyrrolidine,1-(3-aminopropyl)pyrrolidine, 1-(3-(N-methylamino)propyl)pyrrolidine,1-(2-aminoethyl)piperidine, 1-(2-(N-methylamino)ethyl)piperidine,1-(3-aminopropyl)piperidine, 1-(3-(N-methylamino)propyl)piperidine,4-(2-aminoethyl)morpholine, 4-(2-(methylamino)ethyl)morpholine,4-(3-aminopropyl)morpholine, 4-(3-(N-methylamino)propyl)morpholine,1-(2-aminoethyl)-4-methylpiperazine,1-(3-aminopropyl)-4-methylpiperazine,1-(3-(N-methylamino)propyl)-4-methylpiperazine,1-amino-4-methylpiperidine, 1-methylamino-4-methylpiperidine,1-ethyl-4-(N-methylamino)piperidine, 1-methylamino-4-propylpiperidine,1-butyl-4-(N-methylamino)piperidine, 1-(N,N-dimethylamino)piperidine,1-(N,N-diethylamino)piperidine, 4-(pyrrolidin-1-yl)piperidine,4-(piperidin-1-yl)piperidine, 3-aminoquinuclidine,3-(N-methylamino)quinuclidine, aniline, N-methylaniline,N,N-dimethyl-p-phenylenediamine, N,N-dimethyl-m-phenylenediamine,N,N,N′-trimethyl-p-phenylenediamine,N,N,N′-trimethyl-m-phenylenediamine, 1-naphthylamine, 2-naphthylamine,benzylamine, N-methylbenzylamine, phenethylamine,N-methylphenethylamine, 2-picolylamine, 3-picolylamine, 4-picolylamine,N-methyl-2-picolylamine, N-methyl-3-picolylamine,N-methyl-4-picolylamine, 2,5-diazabicyclo[2.2.1]heptane,2-methyl-2,5-diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo[3.2.1]octaneand 1,4-diazabicyclo[4.3.0]nonane.

Examples of the base are the above-described organic bases and inorganicbases, of which, for example, diisopropylethylamine,dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodiumhydride are preferably used. Although there are no specific limitationsto the solvent used for the reaction, a solvent which does not easilyreact with the starting material is desirable. Examples of such solventsare the above-described inert solvents of which, for example,tetrahydrofuran, dichloromethane and N,N-dimethylformamide arepreferably used. The amounts of the amine and the base used for thereaction are 1 to 10 equivalents and 2 to 20 equivalents, respectively,and preferably 1.5 to 5 equivalents and 2 to 10 equivalents,respectively, to the compound of the formula (IIIA). The reaction timeis 10 minutes to 30 hours, and preferably one to two hours. The reactiontemperature is −78° C. to a reflux temperature, and preferably −10° C.to 50° C.

The compound of the formula (IVA) can also be prepared by treating thecompound of the formula (IIA) with an isocyanate in an inert solvent inthe presence of a base and/or cuprous chloride. Although there are nolimitations to the isocyanate, ethyl isocyanate, methyl isocyanate, orphenyl isocyanate can be illustrated by an example. Examples of the baseare the above-described organic bases and inorganic bases, of which, forexample, diisopropylethylamine, dimethylaminopyridine, triethylamine,pyridine, 2,6-lutidine and sodium hydride are preferably used. Althoughthere are no specific limitations to the solvent used for the reaction,a solvent which does not easily react with the starting material isdesirable. Examples of such solvents are the above-described inertsolvents, of which, for example, tetrahydrofuran, dichloromethane andN,N-dimethylformamide are preferably used. The amounts of the base andthe isocyanate used for the reaction are 3 to 100 equivalents and 1 to20 equivalents, respectively, and preferably 5 to 20 equivalents and 3to 10 equivalents, respectively, to the compound of the formula (IIIA).In the case where cuprous chloride is used, the amount thereof is 1 to10 equivalents, and preferably 2 to 6 equivalents. The reaction time is10 minutes to 30 hours, and preferably one to two hours. The reactiontemperature is −78° C. to a reflux temperature, and preferably −10° C.to 50° C.

Further, the compound with a hydroxyl group, in which one or two ofOR^(3X) or^(16X) and OR^(21X) have not been protected in the step A1,can be converted into a derivative having a plurality of urethanestructures, by converting the hydroxyl group into a carbonate group inthe step A3, and then converting the carbonate group into a carbamoyloxygroup in the step A4.

The step A5 is a step of preparing the compound of the formula (VA).This step is carried out by subjecting the urethane derivative of theformula (IVA) to deprotection treatment in an inert solvent in themanner as described below. The reaction for deprotecting the protectivegroup of the hydroxyl group, which varies depending on the type of theprotective group, is carried out by a method well known in the syntheticorganic chemistry.

The deprotection reaction for the respective hydroxyl groups protectedby, for example, 1-ethoxyethyl, tetrahydropyranyl, 1-methoxycyclohexyl,4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl or4-methoxytetrahydrothiopyranyl-S,S-dioxide can be easily carried out byacid-treatment in an inert solvent. As the acid, the above-describedorganic acids and inorganic acids, and the like are used. Preferableexamples include pyridinium p-toluenesulfonate, p-toluenesulfonic acidand camphorsulfonic acid. Although there are no specific limitations tothe solvent used for the reaction, a solvent which does not easily reactwith the precursor is desirable. For example, alcohols solvents such asmethanol, ethanol, isopropanol and tert-butanol are preferable. Thesecan be used in a mixture with the above-described inert solvents. Theamount of acid used for the reaction is 0.5 to 5 equivalents, andpreferably 1 to 3 equivalents, to the compound of the formula (IVA). Thereaction time is 10 minutes to ten days, and preferably one to fourdays. The reaction temperature is −78° C. to a reflux temperature, andpreferably −10° C. to 50° C.

Further, in the case where the hydroxyl group is protected by otherprotective group, for example, tert-butyldimethylsilyl, triethylsilyl,diethylisopropylsilyl, trimethylsilyl, triisopropylsilyl,di-tert-butylmethylsilyl or diphenylmethylsilyl, the protective groupcan be deprotected, for example, by a treatment of a fluorine anion oracid. As the fluorine anion, tetrabutylammonium fluoride, hydrogenfluoride, potassium fluoride and hydrogen fluoride-pyridine are used,for example. As the acid, the above-described organic acids andinorganic acids, and the like are used. Preferable examples includeacetic acid, formic acid, trifluoroacetic acid, pyridiniump-toluenesulfonate and camphorsulfonic acid. Although there are nospecific limitations to the solvent used for the reaction, a solventwhich does not easily react with the starting material is desirable.Examples thereof are the above-described inert solvents, of which, forexample, tetrahydrofuran, diethyl ether and water are preferably used.The amounts of fluorine anion and the acid used for the reaction are 1to 5 equivalents and 0.5 to 5 equivalents, respectively, and preferably1 to 4 equivalents and 0.5 to 3 equivalents, respectively, to thecompound of the formula (IVA). The reaction time is 10 minutes to 30hours, and preferably one to two hours. The reaction temperature is −78°C. to a reflux temperature, and preferably −10° C. to 50° C.

By combining various methods for protecting hydroxyl groups as describedfor the first step with various deprotection methods as described forthe fifth step, each of the hydroxyl groups at the 3-position and the21-position can be selectively subjected to the derivation to obtain theurethane derivative.

In addition, a method for selective modification of the hydroxyl groupat the 3-position or 21-position, conducted by using various combinationof protection and deprotection methods, can also be used for in othermodification methods as described below.B. A Method for Preparing a Thiourethane Derivative

In the formula, R^(3x), R^(16x) and R^(21x) represents the same asdefined above; R^(3c), R^(16c) and R^(21c) independently represents ahydrogen atom, a protective group or a group represented by the formulaR^(N1)R^(N2)N—CS—, wherein R^(N1) and R^(N2) represents the same asdefined above, provided that R^(3c), R^(16c) and R^(21c) do notconcurrently represent a hydrogen atom; and R^(3d), R^(16d) and R^(21d)independently represents a hydrogen atom, or a group represented by theformula R^(N1)R^(N2)N—CS—, wherein R^(N1) and R^(N2) represents the sameas defined above.

The step B1 is a step of synthesizing the compound of the formula (IB)by using an isothiocyanate or a thiocarbamoyl chloride instead of theisocyanate. This step is carried out by treating the compound of theformula (IIA) with an isothiocyanate or a thiocarbamoyl chloride in aninert solvent in the presence of a base or bis(tributyltin)oxide.Although there are no limitations to the isothiocyanate used herein,ethyl isothiocyanate, methyl isothiocyanate, phenyl isothiocyanate,benzyl isothiocyanate, allyl isothiocyanate, 2-(N,N-dimethylamino)ethylisothiocyanate, 2-(N,N-diethylamino)ethyl isothiocyanate,3-(N,N-dimethylamino)propyl isothiocyanate, 3-(N,N-diethylamino)propylisothiocyanate, 2-(morpholin-4-yl)ethyl isothiocyanate,2-(piperidin-1-yl)ethyl isothiocyanate and 2-(pyrrolidin-1-yl)ethylisothiocyanate can be illustrated by examples. Although there are nolimitations to the thiocarbamoyl chloride used herein,N,N-dimethylthiocarbamoyl chloride, N-phenyl-N-methylthiocarbamoylchloride, (morpholin-4-yl)thio carbamoyl chloride,(4-methylpiperazin-1-yl)thio carbamoyl chloride and(4-methylhomopiperazin-1-yl)thio carbamoyl chloride can be illustratedby examples. Examples of the base are the above-described organic basesand inorganic bases, of which, for example, diisopropylethylamine,4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine andsodium hydride are preferably used. Although there are no specificlimitations to the solvent used for the reaction, a solvent which doesnot easily react with the starting material is desirable. Examples ofthe solvent are the above-described inert solvents, of which, forexample, tetrahydrofuran, dichloromethane, N,N-dimethylformamide andtoluene are preferably used. The amounts of base orbis(tributyltin)oxide and the isothiocyanate or thiocarbamoyl chlorideused for the reaction are 1 to 5 equivalents and 1 to 10 equivalents,respectively, and preferably 1 to 3 equivalents and 2 to 5 equivalents,respectively, to the compound of the formula (IIA). The reaction time is10 minutes to 72 hours, and preferably 1 to 24 hours. The reactiontemperature is −78° C. to a reflux temperature, and preferably −10° C.to 70° C.

Further, by converting the hydroxyl group in the compound of the formula(IIA), in which one or two of OR^(3x), OR^(16x) and OR^(21x) have notbeen protected, into a thiocarbamoyloxy group in the step B1, thecompound of the formula (IB) having a plurality of thiocarbamoyl groupscan be synthesized as well.

Subsequently, by removing the protective group(s) of the hydroxylgroup(s) in the step A5, a thiourethane derivative of the formula (IIB)can be synthesized.C. A Method for Preparing an Ether Derivative

In the formula, R^(3e), R^(16e) and R^(21e) independently represent ahydrogen atom or a protective group, provided that R^(3e), R^(16e) andR^(21e) do not concurrently represent a hydrogen atom, and at least oneof R^(3e), R^(16e) and R^(21e) represents a hydrogen atom; R^(3f),R^(16f) and R^(21f) independently represent a protective group or a C₁to C₂₂ alkyl group which may have a substituent; R^(3g), R^(16g) andR^(21g) independently represent a hydrogen atom, an alkyl group or acarbamoyl group; and R^(7g) represents an acetyl group or a carbamoylgroup.

The step C1 is a step of synthesizing a compound of the formula (IC).This step is carried out in a same manner as in the reaction procedurecorresponding to the step A1 of the method A. The number of theprotected hydroxyl groups is one or two, however.

Alternatively, by combining various methods for protecting a hydroxylgroup corresponding to the step A1 of the method A with various methodsfor deprotecting a protected hydroxyl group corresponding to the stepA5, a compound in which one of the substituents at the 3-position and21-position is a hydroxyl group, and the other is a protected hydroxylgroup can be synthesized.

The step C2 is a step of synthesizing a compound of the. formula (IIC).This step is carried out by alkylating the unprotected hydroxyl group(s)in the compound of the formula (IC).

Alkylation can be carried out by treating the compound with analkylating agent of the formula R^(m)—X in the presence of a base. R^(M)represents a C₁ to C₂₂ alkyl group which may have a substituent andincludes, for example, methyl group, ethyl group and benzyl group. Xrepresents a leaving group. Examples of the leaving group include achloro group, bromo group, iodo group and trifluoromethanesulfonylgroup. Examples of the base are the above-described organic bases andinorganic bases, of which preferable examples are sodium hydride,lithium bis(trimethylsilyl)amide, lithium diisopropylamide, lithiumdicyclohexylamide, potassium carbonate, cesium carbonate and1,8-bis(N,N-dimethylamino)naphthalene. Although there are no specificlimitations to the solvent used for the reaction, a solvent which doesnot easily react with the starting material is desirable. Examplesthereof are the above-described inert solvents, of which, for example,diethyl ether, tetrahydrofuran, dimethoxyethane and toluene arepreferably used. The amounts alkylating agent and the base used for thereaction are 3 to 20 equivalents and 5 to 30 equivalents, respectively,and preferably 3 to 5 equivalents and 5 to 10 equivalents, respectively,to the compound of the formula (IC). The reaction time is 10 minutes to48 hours, and preferably 1 to 24 hours. The reaction temperature is −78°C. to a reflux temperature, and preferably −10° C. to 70° C.

The step C3 is a step of synthesizing the compound of the formula(IIIC). In this step, by carrying out the step A2, step A3, step A4 andstep A5 as required, a compound modified by both a carbamoyl group andan alkyl group can be obtained. Further, by carrying out only the stepA5, a compound subjected only to alkylation can be obtained. The step C3can be carried out by applying the reaction conditions of the step A2,step A3, step A4 and step A5.

In the formulas, R^(3x), R^(16x) and R^(21x) are the same as definedabove; and R^(3f′), R^(7f′), R^(16f′) and R^(21′) independentlyrepresent a hydrogen atom or an alkyl group.

Also, an ether derivative represented by the formula (IIC′) in which thehydroxyl group at the 7-position is alkylated can be obtained bysubjecting the compound of the formula (IIA) to the step C2 followed bythe step A5 in the same manner as described above.

Further, in this case, a derivative in which a thiocarbamoyl group isintroduced into the hydroxyl group at the 7-position, and an alkyl groupis introduced into one or two of the hydroxyl groups at the 3-positionand 21-position can be obtained by subjecting the compound of theformula (IIIC) to the step B1 followed by the step A5.

Further, by using an unsaturated alkylating agent, aralkylating agent orheteroaralkylating agent that can produce the desired compound of theformula (I) instead of the above-described alkylating agent, acorresponding ether derivative can be produced.D. A Method for Preparing an Ester Derivative

In the formulas, R^(3e), R^(16e) and R^(21e) independently represent ahydrogen atom or a protective group, provided that R^(3e), R^(16e) andR^(21e) do not concurrently represent a hydrogen atom, and at least oneof R^(3e), R^(16e) and R^(21e) represents a hydrogen atom; and R^(3h),R^(16h) and R^(21h) independently represent a hydrogen atom or a grouprepresented by the formula R^(co)CO—, wherein R^(co) represents ahydrogen atom, a C₁ to C₂₂ alkyl group which may have a substituent, anunsaturated C₂ to C₂₂ alkyl group which may have a substituent, a C₆ toC₁₄ aryl group which may have a substituent, a 5-membered to 14-memberedheteroaryl group which may have a substituent, a C₇ to C₂₂ aralkyl groupwhich may have a substituent or a 5-membered to 14-memberedheteroaralkyl group which may have a substituent, provided that R^(3h),R^(16h) and R^(21h) do not concurrently represent a hydrogen atom.

The step D1 is a step of converting the hydroxyl group, which have notbeen protected, into an ester group using the compound of the formula(IC) synthesized in the step C1 as a starting material.

The esterification reaction is carried out by using an acid anhydrideand a base in combination, an acid halide and a base in combination,carboxylic acid and a condensing agent in combination or Mitsunobureaction, for example. As the acid anhydride, various carboxylicanhydrides are used. Examples include a mixed anhydrides comprising, forexample, acetic acid, propionic acid, butyric acid, valeric acid orbenzoic acid; a symmetrical anhydride; a cyclic anhydride such assuccinic anhydride, glutaric anhydride or adipic anhydride. Aceticanhydride, propionic anhydride, butyric anhydride, benzoic anhydride andthe like are preferable. As the acid halide, for example, various acidchlorides and acid bromides are used, of which a preferred examples areacetyl chloride, propionyl chloride, benzoyl chloride, and benzoylbromide. Examples of the base are the above-described organic bases andinorganic bases, of which, preferred examples are, imidazole,4-dimethylaminopyridine, pyridine and sodium hydride. As the carboxylicacid, various carboxylic acids are used, of which, for example, aceticacid and propionic acid are preferable. As the condensing agent,dicyclohexylcarbodiimide, trifluoroacetic anhydride,carbonyldiimidazole, N,N-diisopropylcarbodiimide and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide are preferable, forexample. In the Mitsunobu reaction, the hydroxyl group can besubstituted by various carboxylic acids in the presence oftriphenylphosphine and diethyl azodicarboxylate or diisopropylazodicarboxylate. Although there are no specific limitations to thesolvent used for each reaction, a solvent which does not easily reactwith the starting material is desirable. Examples thereof are theabove-described inert solvents, of which, for example, dichloromethane,chloroform and tetrahydrofuran are preferable. The amounts of the acidanhydride and the base in combination, the acid halide and the base incombination and the carboxylic acid and the condensing agent incombination, which are used for the reaction, are 1 to 10 equivalentsand 3 to 20 equivalents in combination, 1 to 10 equivalents and 3 to 20equivalents in combination, and 1 to 20 equivalents and 1 to 20equivalents in combination, respectively, and preferably 1 to 5equivalents and 2 to 10 equivalents in combination, 1 to 5 equivalentsand 2 to 10 equivalents in combination, and 1 to 5 equivalents and 1 to5 equivalents in combination, respectively, to the compound of theformula (IC). Further, the reaction can be accelerated by addition of0.2 to 2 equivalents of 4-dimethylaminopyridine as required. Thereaction time is 10 minutes to 30 hours, and preferably one to twohours. The reaction temperature is −78° C. to a reflux temperature, andpreferably −10° C. to 50° C.

Subsequently, by removing the protective group for the hydroxyl group ofthe thus-synthesized ester derivative by the same reaction procedure asdescribed for the step A5, a compound of the formula (ID) can beproduced.

In addition, by carrying out the same esterification reaction as in thestep D1 using 6-deoxy 11107D as a starting material, one to threehydroxyl groups can also be esterified.

In the formula, R^(3x), R^(6x) and R^(21x) are the same as definedabove; and R^(3h′), R^(7h′), R^(16h′) and R^(21h′) independentlyrepresent a hydrogen atom or a group represented by the formulaR^(co)CO—, wherein R^(co) represents the same group as defined above.

Further, a derivative represented by the formula (ID′) in which thehydroxyl group at the 7-position is esterified can be obtained bysubjecting the compound of the formula (IIA) to the step D1 in the samemanner as described above, and then subjecting the product to the stepA5.E. A Method for Preparing a Phosphate Ester Derivative or AmidophosphateEster Derivative

In the formula, R^(3x), R^(16x) and R^(21x) are the same as definedabove; and R^(3i), R^(7i), R^(16i) and R^(21i) independently represent ahydrogen atom, a group represented by the formula (R^(N3)O)₂PO—,(R^(N1)R^(N2)N)₂PO—, or (R^(N1)R^(N2)N)(R^(N3)O)PO—, wherein R^(N1),R^(N2) and R^(N3) are the same meanings as defined above.

The step E1 is a step for converting the hydroxy group of the compoundof formula (IIA) as starting material into phosphoric ester oramidophosphoric ester.

The phosphoric-esterification is carried out using phosphoryl halide anda base, for example. As the phosphoryl halide, various types can be usedherein, and examples thereof include a dialkoxyphosphoryl chloride, adiphenyloxyphosphoryl chloride, an alkoxy(N,N-disubstitutedamino)phosphoryl chloride, an allyloxy(N,N-disubstitutedamino)phosphoryl chloride, an alkoxy(N-substituted amino)phosphorylchloride and allyloxy(N-substituted amino)phosphoryl chloride. Examplesof the base are the above-described organic bases and inorganic bases,of which preferred examples are pyridine, 4-dimethylaminopyridine,triethylamine, ethyldiisopropylamine, sodium hydride, n-butyl lithium,potassium carbonate and sodium carbonate. Although there are no specificlimitations to the solvent used for each reaction, a solvent which doesnot easily react with the starting material is desirable. Examplesthereof are the above-described inert solvents, of which, for-example,dichloromethane, chloroform, tetrahydrofuran and N,N-dimethylformamideare preferably used. The reaction time is 10 minutes to 72 hours, andpreferably 1 to 24 hours. The amounts of the phosphorus halide and thebase used for the reaction are 1 to 10 equivalents and 2 to 20equivalents, respectively, and preferably 1 to 5 equivalents and 2 to 10equivalents, respectively, to the compound of the formula (IIA). Thereaction temperature is −78° C. to a reflux temperature, and preferably−10° C. to 50° C.

Subsequently, by removing the protective group for the hydroxyl group inthe thus-synthesized phosphoric ester derivative by a similar reactionprocedure as in the step A5, a compound of the formula (IE) can beprepared.

In addition, by carrying out the same phosphoric-esterification as inthe step E1 using 6-deoxy 11107D as a starting material, one to four ofthe hydroxyl groups can also be phosphoric-esterified.F. A Method for Preparing a Sulfuric Ester Derivative or AmidosulfuricEster Derivative

In the formula, R^(3x), R^(16x) and R^(21x) are the same as definedabove; and R^(3j), R^(7j), R^(16j) and R^(21j) independently represent ahydrogen atom or a group represented by the formula R^(N1)R^(N2)N—SO₂—or R^(N4)O—SO₂—, wherein R^(N1), R^(N2) and R^(N4) independentlyrepresent the same group as defined above.

The step F1 is a step for converting the hydroxyl group of the compoundof the formula (IIA) as a starting material into sulfuric ester.

The sulfuric-esterification is carried out using sulfuric halide and abase or the like. As the sulfuric halide, various types can be used.Examples include alkoxysulfonyl chloride and N,N-disubstituted sulfamoylchloride. As the base, the above-described organic bases and inorganicbases, and the like can be used. For example, pyridine,4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, sodiumhydride, n-butyl lithium, potassium carbonate and sodium carbonate arepreferable. Although there are no specific limitations to the solventused for each reaction, a solvent which does not easily react with theprecursor is desirable. The above-described inert solvents can be used.Preferably, for example, dichloromethane, chloroform, tetrahydrofuranand N,N-dimethylformamide are used. The amounts of the sulfuric halideand the base used for the reaction are 1 to 10 equivalents and 2 to 20equivalents, respectively and preferably 1 to 5 equivalents and 2 to 10equivalents, respectively, to the compound of the formula (IIA). Thereaction time is 10 minutes to 72 hours, and preferably 1 to 24 hours.The reaction temperature is −78° C. to a reflux temperature, andpreferably −10° C. to 50° C.

Subsequently, by removing the protective group for the hydroxyl group inthe thus-synthesized sulfuric ester derivative by the similar reactionmanner as in the step A5, a compound of the formula (IF) can besynthesized.

In addition, by carrying out the similar sulfuric esterification as inthe step F1 using 6-deoxy 11107D as a starting material, one to four ofthe hydroxyl groups can also be sulfuric-esterified.G. A Method for Preparing a Halogen Derivative

In the formulas, R^(3x), R^(16x) and R^(21x) are the same as definedabove; and R^(3k), R^(16k) and R^(21k) independently represent ahydroxyl group or a halogen atom.

The step G1 is a step of converting a hydroxyl group into halogen usingthe compound of the formula (IA) as a starting material.

This halogenation reaction can be carried out by treatingdiethylaminosulfur trifluoride (DAST) or triphenylphosphine with carbontetrabromide, bromine, phosphorus tribromide, iodine or carbontetrachloride in the presence of a base, for example. As the base,common organic bases and inorganic bases, for example,diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine,2,6-lutidine and sodium hydride can be used. Although there are nospecific limitations to the solvent used for the reaction, a solventwhich does not easily react with the precursor is desirable. Examplesinclude tetrahydrofuran, dichloromethane and N,N-dimethylformamide. Inparticular, fluorination reaction using diethylaminosulfur trifluorideis preferable. The amount of diethylaminosulfur trifluoride (DAST) usedfor the reaction is 1 to 5 equivalents, and preferably 1 to 3equivalents, to the compound of the formula (IA). The reaction time is10 minutes to 10 hours. The reaction temperature is −78° C. to roomtemperature.

Subsequently, by removing the protective group for the hydroxyl group(s)in the thus-synthesized halogen derivative by the step A5, a compound ofthe formula (IG) can be synthesized.H. A Method for Preparing a Sulfonic Ester Derivative

In the formulas, R^(3x), R^(16x) and R^(21x) are the same as definedabove; and R^(1l), R^(7l), R^(16l) and R^(21l) independently represent ahydrogen atom or a group represented by the formula R^(N5)SO₂—, whereinR^(N5) represents the same as defined above.

The step H1 is a step of sulfonylation of a hydroxyl group using thecompound of the formula (IIA) as a starting material.

The sulfonylation can be carried out by treating sulfonyl chlorides suchas p-toluenesulfonyl chloride, methanesulfonyl chloride andbenzenesulfonyl chloride, for example, in the presence of a base. As thebase, general organic bases and inorganic bases, for example,diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine,2,6-lutidine and sodium hydride can be used. Although there are nospecific limitations to the solvent used for the reaction, a solventwhich does not easily react with the starting material is desirable.Examples include tetrahydrofuran, dichloromethane andN,N-dimethylformamide. The amounts of the sulfonyl chloride and the baseused for the reaction are 1 to 5 equivalents and 2 to 10 equivalents,respectively, and preferably 1 to 3 equivalents and 2 to 6 equivalents,respectively, to the compound of the formula (IIA). The reaction time is10 minutes to 30 hours. The reaction temperature is −78° C. to a refluxtemperature.

Subsequently, by removing the protective group for the hydroxyl group inthe thus-synthesized sulfonate derivative by the step A5, a derivativerepresented by the formula (IH), in which the hydroxyl group at the7-position is sulfonylated, can be synthesized.

In addition, by carrying out the same sulfonylation as in the step H1using 6-deoxy 11107D as a starting material, one to four of the hydroxylgroups can also be sulfonylated.I. A Method for Preparing an Amine Derivative

In the formulas, R^(3x), R^(16x) and R^(21x) are the same as definedabove; and R^(3m), R^(7m), R^(16m) and R^(21m) independently represent ahydroxyl group or a group of the formula R^(N1)R^(N2)N—, wherein R^(N1)and R^(N2) represent the same as defined above.

The step I1 is a step of converting a hydroxyl group directly intoamine, or a step of converting a hydroxyl group into a good leavinggroup, then converting the leaving group into azide, and subsequentlyconverting the azide into amine by reduction, using the compound of theformula (IIA) as a starting material.

In the case where the hydroxyl group is converted into an azide, 1)diphenylphosphoryl azide (DPPA), diethyl azodicarboxylate andtriphenylphosphine, 2) DPPA and 1,8-diazabicyclo[5.4.0]undeca-7-ene(DBU), 3) hydrogen azide, diethyl azodicarboxylate andtriphenylphosphine, 4) DPPA, tetramethylazodicarboxamide (TMAD) andtributylphosphine or 5) sodium azide in the presence of a base can beused, for example. As the base, the above-described organic bases andinorganic bases, and the like can be used. Preferably, for example,diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine,2,6-lutidine and sodium hydride are used. Further, the hydroxyl groupcan be also converted into azide by treating with sodium azide in thepresence of the palladium catalyst. Examples of the palladium catalystinclude Pd(PPh₃)₄. Although there are no specific limitations to thesolvent used for the reaction, a solvent which does not easily reactwith the starting material is desirable. Examples includetetrahydrofuran, dichloromethane, N,N-dimethylformamide, toluene andbenzene. The reaction time is 10 minutes to 30 hours. The reactiontemperature is −78° C. to a reflux temperature.

The reduction of azide into amine can be carried out by usingtriphenylphosphine or lithium aluminum hydride, for example. Inaddition, the reduction to amine can also be carried out using acatalyst such as palladium carbon or a Lindlar catalyst under hydrogenatmosphere. Although there are no specific limitations to the solventused for the reaction, a solvent which does not easily react with thestarting material is desirable. Examples include tetrahydrofuran,diethyl ether and ethanol. The reaction time is 10 minutes to 30 hours.The reaction temperature is −78° C. to a reflux temperature.

The hydroxyl group can be converted into a good leaving group accordingto a similar manner as described for the step G1 (halogenation) or stepHi (sulfonylation). Examples of the good leaving group include a chlorogroup, bromo group, iodo group, methanesulfonyl group andp-toluenesulfonyl group.

Subsequently, by treating this compound in which the hydroxyl group isconverted into a leaving group with amine in an inert solvent in thepresence of a base, a compound in which the hydroxyl group is convertedinto an amino group or an amino group having a substituent can besynthesized.

Examples of the amine used include methylamine, ethyl amine,dimethylamine and diethylamine. As the base, the above-described organicbases and inorganic bases, and the like can be used. Preferably, forexample, diisopropylethylamine, dimethylaminopyridine, triethylamine,pyridine, 2,6-lutidine and sodium hydride are used. Although there areno specific limitations to the solvent used for the reaction, a solventwhich does not easily react with the starting material is desirable. Theabove-described inert solvents can be used. Preferably, for example,tetrahydrofuran, dichloromethane and N,N-dimethylformamide are used. Thereaction time is 10 minutes to 30 hours, and preferably one to twohours. The reaction temperature is −78° C. to a reflux temperature, andpreferably −10° C. to 50° C.

Subsequently, by removing the protective group for the hydroxyl group inthe thus-synthesized amine derivative synthesized by a similar manner asin the step A5, a compound of the formula (II) can be prepared. Inaddition, by carrying out the same amination procedure as in the step I1using 6-deoxy 11107D as a starting material, one or two hydroxyl groupscan also be aminated.

Further, by alkylating, acylating, carbamoylating or sulfonylating theamino group respectively in the compound of the formula (II) using amethod well known in the synthetic organic chemistry or theabove-described method, the compound of the formula (I) can be prepared.J. A Method for Preparing a Keto Compound (Oxidation of a HydroxylGroup)

In the formula, any one of R^(3Ja) and R^(3Ja) represents a hydroxylgroup, and the other represents a hydrogen atom, or R^(3Ja) and R^(3Ja),together in combination with the carbon atom to which R^(3Ja) andR^(3Ja) are bonded, represent an oxo group; and any one of R^(21Ja) andR^(21Ja) represents a hydroxyl group, and the other represents ahydrogen atom, or R^(21Ja) and R^(21Ja), together in combination withthe carbon atom to which R^(21Ja) and R^(21Ja) are bonded, represent anoxo group.

The step J1 is a step of synthesizing an oxo-compound represented by theformula (IIJ) by oxidation of the hydroxyl group of 6-deoxy 11107D as astarting material.

The oxidizing agent used in this step is, for example, manganesedioxide, pyridinium chlorochromate, pyridinium dichromate, Dess-Martinreagent or reagents used in Swern oxidation. Although there are nospecific limitations to the solvent used for the reaction, a solventwhich does not easily react with the starting material is desirable.Examples include tetrahydrofuran, dichloromethane, chloroform andtoluene. The reaction temperature is −78° C. to a reflux temperature.The reaction time is 10 minutes to 78 hours. Above all, a reaction usingDess-Martin reagent, manganese dioxide or reagents under Swern oxidationis preferable, for example. A reaction using Dess-Martin reagent isparticularly preferable. As the solvent in the oxidation usingDess-Martin reagent, dichloromethane and chloroform are particularlypreferable. The amount of the oxidizing agent used herein is 1 to 20equivalents, and preferably 1 to 5 equivalents, to the compound (6-deoxy11107D). The reaction temperature is preferably 0° C. to roomtemperature. The reaction time is 30 minutes to 24 hours, and preferablyone to eight hours.

Further, in the step J1, by using a compound obtained by preliminaryderivation by the above-described method for an urethane derivative,thiourethane derivative, ester derivative, alkyl derivative, or thelike, instead of 6-deoxy 11107D, a compound in which the hydroxyl groupat the 3-position or 21-position of these derivatives is converted intoan oxo moiety can be synthesized. In addition, by oxidizing the hydroxylgroup at the 7-position of the compound represented by the formula(IIA), a 7-oxo compound can also be obtained.

Moreover, by combining protection and deprotection procedures of theabove-described steps A1 and A5 with the step J1 in various manners, thehydroxyl groups at the 3-position, the 7-position and/or the 21-positioncan be selectively converted into an oxo moiety. Further, by conductingurethane derivation, thiourethane derivation, ester derivation or alkylderivation of a compound respectively, of which the hydroxyl group ispreliminarily converted into an oxo moiety, according to theabove-described method, a compound modified by both the correspondingmodification and the oxo-derivatization can be synthesized,respectively.

By an appropriate combination of the reactions A to J and the protectionand deprotection procedures of the hydroxyl group as described above,the compound represented by the formula (I) can be synthesized.

After termination of the reaction, the target product of each reactionis isolated from a reaction mixture according to a conventionalprocedure. For example, the target product can be obtained by removingan insoluble matter by filtration and removing the solvent byevaporation in an appropriate manner, if insoluble matter is present, orby diluting the reaction mixture with an organic solvent such as ethylacetate, washing the mixture with water, drying the organic layer withanhydrous magnesium sulfate, and then evaporation. If required, thetarget product can be further purified by a conventional procedure, forexample, column chromatography, thinlayer chromatography or highperformance liquid-chromatography.

The compound of the formula (I) can be synthesized from the isolated andpurified 6-deoxy 11107D and 6-deoxy 11107D compound using a commonorganic synthetic procedure. Representative A. urethane derivatives, B.thiourethane derivatives, C. ether derivatives, D. ester derivatives, E.phosphoric ester derivatives or monoamidosulfuric ester derivatives, F.sulfonic ester derivatives and amidosulfonic ester derivatives, G.halogen derivatives, H. sulfonate derivatives, I. amine derivatives andJ. keto compounds can be produced in the above-described methods bychanging the conditions of the step 1A of protecting a hydroxyl group.

Next, in order to prove the usefulness of the present invention, VEGFtranscription inhibitory action, action of inhibiting proliferation ofWiDr human colon cancer cells, solid cancer proliferation inhibitoryaction, body weight reduction (acute toxicity) and stability in anaqueous solution of compounds as representatives of the compound of theformula (I) of the present invention were measured.

Test Example 1 Construction of a Reporter System for Screening aCompound Inhibiting VEGF Transcription

In order to prepare a reporter system in which transcription from a VEGFpromoter is reflected, a VEGF promoter sequence was cloned and insertedinto a placental alkaline phosphatase (PLAP) vector to construct areporter vector.

In order to obtain a promoter region of human VEGF, a VEGF genome wascloned from a phage library. Based on VEGF cDNA (GenBank accessionnumber: X62568), a PCR primer in the sequence described as SEQ ID NO: 1or SEQ ID NO: 2 was designed to conduct PCR, thereby obtaining about afragment of 340 bp. A human genomic phage library (human genomiclibrary, Clontech) was screened using this fragment as a probe to obtainpUC18-VEGFA containing a VEGF5′ franking region of about 5.4 kb. ThispUC18-VEGFA was cut with KpnI/NheI to obtain a VEGF promoter region ofabout 2.3 kb, and the region was inserted into the multicloning siteKpnI/NheI of the placental alkaline phosphatase (PLAP) reporter vector(Goto et al., Mol. Pharmacol., 49, 860-873, 1996) to construct aVEGF-PLAP vector.

The above-described VEGF-PLAP vector was introduced into U251 cellscultured in a Dulbecco's modified Eagle's medium containing 10% fetalbovine serum (DMEM, manufactured by Sigma Co.), and cultured in thepresence of 1 mg/mL G418 (Merck & Co., Inc.) to establish aG418-resistant stable clone (U251/1-8 cells).

As in a report by Minchenko et al. (Cell. Mol. Biol. Res., 40, 35-39,1994), U251/1-8 cells were confirmed to be a reporter system whichsecretes PLAP into a culture medium under hypoxic conditions (2% O₂incubator), and in which transcription from a VEGF promoter isreflected. A compound inhibiting VEGF production induced by hypoxicstimulation was screened using this clone.

Test Example 2 VEGF Transcription Inhibitory Activity of a 6-Deoxy11107D Derivative

In order to eliminate influence of the alkali phosphatase in the serum,the U251/1-8 cells were washed with a sufficient amount of PBS(Phosphate buffered saline) twice, and treated at 65° C. for 20 minutesto inactivate the alkaline phosphatase in the serum. 4×10⁴ cells/180 μLper well of the cells diluted in the DMEM culture medium containing 10%of this serum were plated in a 96-well plate.

The cells were cultured in a CO₂ incubator (5% CO₂) at 37° C. overnight,and 20 μL of the above-described culture solution containing the testcompound at threefold serial dilutions was added. Subsequently, thecells were cultured in hypoxic (2% O₂) incubator for 18 hours. Tomeasure the PLAP activity in the culture supernatant liquid, 10 μL ofthe culture supernatant liquid was added to 50 μL of a 0.28 MNa₂CO₃—NaHCO₃ buffer solution (pH 10.0, 8.0 mM MgSO₄), and finally 50 μLof an alkaline phosphatase substrate (Lumistain, Genome ScienceLaboratories Co., Ltd.) was added thereto. After the reaction for onehour, chemiluminescence was detected using a microplate reader(PerkinElmer) to measure the PLAP activity as the alkaline phosphataseactivity. The PLAP activity under normoxic conditions was defined as 0%,the PLAP activity of the cells when treated under hypoxic conditions wasdefined as 100%, and the concentration for inhibiting 50% of the PLAPactivity was defined as the IC₅₀ value of PLAP. The IC₅₀ values of the6-deoxy 11107D derivatives shown in examples were determined (n=2 to 3).The IC₅₀ values of the representative compounds are shown in Table 1.TABLE 1 VEGF transcription inhibitory Test compound activity (IC₅₀: nM)Compound 18** 1.0 Compound 19* 1.1 Compound 20** 1.1 Compound 21** 2.0Compound 22** 2.5 Compound 23* 14.7 Compound 29** 1.3 Compound 39** 1.3Compound 43* 2.3 Compound 44* 2.4 Compound 55** 1.1

The compound of the formula (I) exhibited strong VEGF transcriptioninhibitory activity.

Test Example 3 Action of Inhibiting Proliferation of WiDr Human ColonCancer Cells

2×10³ cells/well of WiDr human colon cancer cells cultured in aDulbecco's modified Eagle's medium containing 10% fetal bovine serum,penicillin (100 units/mL) and streptomycin (100 μg/mL) (DMEM,manufactured by Sigma Co.) were plated in a 96-well plate. The cellswere cultured in a CO₂ incubator overnight, and 20 μL of theabove-described culture solution containing the test compound atthreefold serial dilutions was added for culturing the cells. Afterthree days, 50 μL of a 3.3 mg/mL MTT solution was added, and the cellswere further cultured for one hour. Then, formazan generated byreduction using living cells was extracted with 100 μL of DMSO tomeasure the absorbance (A540/A660), which was used as an index of thenumber of living cells.

The concentration for inhibiting 50% of proliferation of WiDr humancolon cancer cells (IC₅₀ value) of the compound of the formula (I) wasdetermined (n=2 to 3). The IC₅₀ values of the representative compoundsare shown in Table 2. TABLE 2 WiDr human colon cancer cell proliferationinhibitory activity Test compound (IC₅₀: nM) Compound 18** 0.5 Compound19* 0.3 Compound 20** 0.2 Compound 21** 0.6 Compound 22** 1.1 Compound23* 3.8 Compound 29** 0.3 Compound 39** 0.5 Compound 43** 0.5 Compound44* 0.6 Compound 55** 0.6

The compound of the formula (I) exhibited strong WiDr human colon cancercell proliferation inhibitory action.

Test Example 4 Solid Cancer Growth Inhibitory Action

In order to examine the solid cancer growth inhibitory activity of thecompound of the formula (I) in vivo, WiDr human colon cancer cells weresubcutaneously implanted into the body of each nude mouse. When thetumor volume of each mouse reached about 100 mm3, the mice wereclassified into groups so that both groups had an uniform average tumorvolume of the mice. The control group consisted of ten mice, and the6-deoxy 11107D derivative-administration group consisted of five mice.The derivative was intravenously injected at 0.625 mg/kg/day, 1.25mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day, or 10 mg/kg/day to each mouse ofthe administration group, and a vehicle was administered to each mouseof the control group.

The tumor volumes on the 15th day were measured to determine therelative tumor weight ratio (T/C %), based on the tumor weight of eachmouse of the control group as 100%. Each T/C % for the representativecompounds of the formula (I) is shown in Table 3. The body weights onthe day of the start of administration, 5th day, 8th day, 12th day and15th (or 16th) day were measured to examine the relative body weightvariations in the case of administering the representative compounds,based on the body weights on the day of the start of administration as100%. The minimum relative body weight ratios, which are the relativebody weight ratios on the day when the body weights were lightest, areshown in Table 3. TABLE 3 WiDr human colon tumor growth Minimum Amountinhibitory relative Test administered activity body weight compound(mg/kg/day) T/C(%) ratio Compound 43 1.25 9 0.83 Compound 55 0.625 110.80

The compound of the formula (I) exhibited action for inhibiting growthof WiDr human colon tumors even in vivo at a dose not causing asignificant reduction in the body weight.

Test Example 5 Stability in an Aqueous Solution

The compound of the formula (I) was dissolved in DMSO at a concentrationof 10 to 20 mM, and the solution was diluted with a pH 7Britton-Robinson buffer solution to about 500-fold. This solution wasused as a sample solution, and was incubated at 25° C. for 24 hours.

The sample solution before and after the incubation was analyzed usinghigh-performance liquid chromatography to obtain a chromatogram. Thepercentage of the compound remaining in the sample solution after theincubation was determined from the peak area of the chromatogram. Theresults for the representative compounds are shown in Table 4. TABLE 4Remaining Test compound percentage (%) FD-895 83.0 Compound 18 95.0Compound 19 95.5 Compound 20 95.6 Compound 21 94.8 Compound 22 95.4Compound 39 95.9 Compound 43 95.8 Compound 44 95.4 Compound 55 95.7

While the content of FD895 was decreased to 83% after 24 hours, theremaining percentages of the compounds 18, 19, 20, 22, 39, 43, 44 and 55as the representatives of the compound of the formula (I) were all 95 to96%. This data indicates that the 6-deoxy 11107D derivative as thecompound of the formula (I) are stable in aqueous solutions.

As is clear from the above-described pharmacological test examples, thecompound of the formula (I) of the present invention alters geneexpression, and thus inhibits VEGF production, in particular. Therefore,the compound is expected to be used as a tumor treating agent, inparticular, a solid cancer treating agent, cancer metastasis inhibitor,diabetic retinopathy treating agent, rheumatoid arthritis treating agentor ecchymoma treating agent. Furthermore, as can be seen in the toxicitytest in Test Example 4, since the action of inhibiting growth of WiDrhuman colon cancer tumors is exhibited at a dose not causing asignificant reduction in the body weights of the test mice, the compoundof the formula (I) is a compound which is highly safe. Accordingly, thecompound is effective for preventing or treating a disease for whichgene expression control is effective, a disease for which VEGFproduction inhibitory action is effective, and a disease for whichangiogenesis inhibitory action is effective. The “prevention ortreatment” refers to prevention, treatment, or both. More specifically,the compound of the formula (I) of the present invention is effective asan antitumor drug, in particular, an antitumor drug or tumor metastasisinhibitor against a solid cancer. Examples of the solid cancer include apancreatic cancer, stomach cancer, colon cancer, breast cancer, prostatecancer, lung cancer, renal cancer, brain tumor, head and neck cancer,esophagus cancer, skin cancer, hepatic cancer, uterine cancer, cancer ofthe uterine cervix, bladder cancer, thyroid cancer, testicular tumor,villus cancer, osteosarcoma, soft-tissue sarcomata and ovarian cancer.The compound is particularly preferably used for cancers such as a coloncancer, breast cancer, prostate cancer, lung cancer, head and neckcancer, and ovarian cancer. Further, the compound is also effective asan anticancer drug against leukemia. In addition, the compound is alsoeffective as a hemangioma treating agent. Moreover, the compound iseffective as a diabetic retinopathy treating agent, rheumatoid arthritistreating agent or hemangioma treating agent based on the VEGF productioninhibitory action. Alternatively, the compound is also effective as anagent for treating inflammatory diseases consisting of osteoarthritis,psoriasis, delayed hypersensitive reaction and atherosclerosis.

When the above-described compound is to be prepared as an injectablesolution, a pH adjuster, buffering agent, stabilizer, solubilizer, orthe like are added to the active ingredient, as required, to prepare aninjectable solution for subcutaneous, intramuscular, intra-articular orintravenous administration.

When the above-described compound is to be administered as an agent fortreating or preventing various diseases, the compound may be orallyadministered as tablets, powder, granules, capsules, syrup, or the like,or the compound may be parenterally administered as a spray, asuppository, an injectable solution, an external use or drops. The dosesignificantly varies according to the degree of symptom, the age, thetype of liver disease, and the like, the dose for the adult is typicallyabout 1 mg to 100 mg per day in a single dose or in divided doses ofseveral times.

A drug product is produced using general ingredients in a conventionalmethod. Specifically, when an oral solid formulation is to be prepared,a vehicle and, as required, a binder, disintegrating agent, lubricant,coloring agent, flavoring or odor-masking agent, or the like are addedto the active ingredient, and then the mixture is fabricated intotablets, coated tablets, granules, powder, capsules, or the like. Thesetablets or granules may be appropriately coated with sugar, gelatin, orother coatings, naturally.

According to the present invention, the compound of the formula (I) ofthe present invention inhibits VEGF production and angiogenesis, inparticular, by altering gene expression, exhibits an excellent antitumoreffect in a in vivo solid cancer model, and also has stability in anaqueous solution. Therefore, the present invention can provide a cancertreating agent, in particular, a solid cancer treating agent, cancermetastasis inhibitor, diabetic retinopathy treating agent, rheumatoidarthritis treating agent or ecchymoma treating agent, for example.

EXAMPLES

The present invention will be described in more detail below withreference to examples consisting of methods for producing 6-deoxy 11107B(Examples 1 to 4), bioconversion reactions from 6-deoxy 1107B to 6-deoxy11107D (Examples 5 to 11), 6-deoxy 11107D analogues (Examples 12 to 17)and 6-deoxy 11107D derivatives (Examples 18 to 60), as well as referenceexamples. However, the present invention should not be limited to theseexamples.

The abbreviations used in the chemical formulas of the examples areshown below.

DEIPS: Diethylisopropylsilyl group

EE: 1-Ethoxyethyl group

TES: Triethylsilyl group

Example 1 Acquisition of a Mutant of Mer-11107

In the present invention, Streptomyces sp. Mer-11107 (depositary number:FERM BP-7812) was mutated with N-methyl-N′-nitroso-N-nitrosoguanidine ina Tris-maleate buffer solution (pH 6.0) (100 μg/mL, 28° C., one hour),and the strain was smeared on an yeast-malt agar culture medium to formspores. The resulting spores were collected, and a part of the sporeswere diluted and smeared on an yeast-malt agar culture solution to formcolonies. Each cell as sampled from colonies, inoculated into a 15mL-volume test tube containing 2 mL of a seed culture medium (glucose:2%, soybean meal (Esusan meat, manufactured by Ajinomoto Co., Inc.): 1%,yeast extract (manufactured by Oriental Yeast Co., Ltd.): 0.5%, sodiumchloride: 0.25% and calcium carbonate: 0.32%, pH 6.8), and cultured on ashaking culture apparatus at 25° C. for two days. Further, 0.5 mL of theseed culture solution (of which the remainder was frozen) was inoculatedinto a 15 mL-volume test tube containing 2 mL of a production culturemedium (soluble starch: 7%, gluten meal: 0.8%, pharmamedia: 0.8% andcalcium carbonate: 0.1%; pH 7.5), and the cells were cultured on ashaking culture apparatus at 25° C. for four days. The culture solutionwas extracted with ethyl acetate, and analyzed by TLC (Merck 5715,acetone:toluene=1:1, colored with phosphomolybdic acid) to select thestrain A-1543, a strain in which a spot other than 11107B (Rf: about0.5) appeared. This strain was deposited with International PatentOrganism Depositary, National Institute of Advanced Industrial Scienceand Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki305-8566, Japan as FERM P-18942 on Jul. 23, 2002, and was transferred toInternational Patent Organism Depositary (IPOD), National Institute ofAdvanced Industrial Science and Technology in Central 6, 1-1-1 Higashi,Tsukuba-shi, Ibaraki 305-8566, Japan under the international depositarynumber FERM BP-8442 on Jul. 28, 2003.

Example 2 Culture of A-1543

A frozen seed culture of A-1543 in advance was melted. 0.2 mL of themelt was inoculated into a 250 mL-volume conical flask containing 20 mLof a seed culture medium (glucose: 2%, soybean meal (Esusan meat,manufactured by Ajinomoto Co., Inc.): 1%, yeast extract (manufactured byOriental Yeast Co., Ltd.): 0.5%, sodium chloride: 0.25% and calciumcarbonate: 0.32%; pH 6.8), and the cells were cultured on a shakingculture apparatus at 25° C. for three days. Further, 0.6 mL of the seedculture solution was inoculated into a 60 mL of a production culturemedium (soluble starch: 5%, gluten meal: 1%, pharmamedia: 2% and calciumcarbonate: 0.1%; pH 7.5), and the seed mash was cultured on a shakingculture apparatus at 25° C. for five days.

Example 3 Purification of 6-Deoxy 11107B and 6-Deoxy 11107BI

The culture solution prepared by the method of Example 2 (1.2 L) wasseparated into a filtrate and cells using a centrifuge. The supernatantliquid was extracted with ethyl acetate (1.2 L). The cells wereextracted with acetone (500 mL), and the extract was filtrated to obtainan acetone extract. Acetone of the acetone extract was removed bydistillation under reduced pressure, and then the distilled product wasextracted with ethyl acetate (1 L). The respective ethyl acetate layerwas washed with water, and dried by dehydration with anhydrous sodiumsulfate. Then, these layers were concentrated together under reducedpressure to obtain 531 mg of a crude active fraction. This crude activefraction was subjected to silica gel column chromatography (Kiesel gel60, 25 g), washed with toluene (50 mL), and eluted with a mixed solutionof toluene with ethyl acetate (3:1; v/v)(300 mL) to obtain 161 mg of acrude active fraction containing 6-deoxy 11107B and 34 mg of a crudeactive fraction containing 6-deoxy 11107B1. The resulting crude activefraction containing 6-deoxy 11107B was subjected to preparativehigh-performance liquid chromatography (HPLC) under the preparativeconditions (A1) described below to obtain a 6-deoxy 11107B fractioneluted. Then, the solvent was removed by distillation to obtain 118.8 mgof 6-deoxy 11107B. Similarly, the crude active fraction containing6-deoxy 11107BI was fractionated using HPLC under the preparativeconditions (A2) described below, and then the solvent was removed bydistillation to obtain 11.0 mg of 6-deoxy 11107BI.

Preparative HPLC Conditions (A1)

-   Column: CAPCELL PAK C18 UG120, diameter: 30 mm, length: 250 mm    (manufactured by Shiseido Co., Ltd.)-   Flow rate: 20 mL/min-   Detection: 240 nm-   Eluate: Acetonitrile/water (60:40, v/v), isocratic    Preparative HPLC Conditions (A2)-   Column: CAPCELL PAK C18 UG120, diameter: 30 mm, length: 250 mm    (manufactured by Shiseido Co., Ltd.)-   Flow rate: 20 mL/min-   Detection: 240 nm-   Eluate: Acetonitrile/water (65:35, v/v), isocratic

The retention time of the above-described compounds when analyzed underthe following analytical HPLC conditions is shown below. Analytical HPLCconditions (a)

-   Column: CAPCELL PAK C18 SG120, diameter: 4.6 mm, length: 250 mm    (manufactured by Shiseido Co., Ltd.)-   Temperature: 40° C.-   Flow rate: 1 mL/min-   Detection: 240 nm-   Eluate: Acetonitrile/water (60:40, v/v), isocratic-   Retention time:-   6-deoxy 11107B: 12.0 minutes-   6-deoxy 11107BI: 26.4 minutes

Example 4 Physicochemical Properties of 6-Deoxy 11107B

Physicochemical properties of 6-deoxy 11107B are shown below. 6-deoxy11107B was determined to have a structure represented by the formula(XVI″).

1. Characteristics: Colorless powder

2. Molecular weight: 520, ESI-MS 543 (M+Na)⁺, ESI-MS 519 (M−H)⁻

3. Solubility: soluble in dimethyl sulfoxide, pyridine, methanol, andacetone, poorly soluble in water

4. Color reaction: Positive for iodine, sulfuric acid, andphosphomolybdic acid

5. Ultraviolet spectrum (methanol, maximum value) nm: 240 (ε33500)

6. Infrared absorption spectrum (KBr)cm⁻¹: 3449, 2965, 1734, 1456, 1372,1242, 1170

7.

¹H-NMR spectrum (CD₃OD, 400 MHz): δ ppm (integration, multiplicity,coupling constant J (Hz)): 0.87 (3H, d, J=7.0 Hz), 0.90 (3H, d, J=7.0Hz), 0.94 (3H, d, J=7.3 Hz), 0.97 (3H, d, J=7.0 Hz), 1.08 (3H, d, J=7.0Hz), 1.17-1.21 (1H, m), 1.24-1.36 (2H, m), 1.42-1.52 (3H, m), 1.61-1.66(3H, m), 1.74 (3H, d, J=1.1 Hz), 1.89-1.96 (1H, m), 2.00 (3H, s),2.41-2.47 (1H, m), 2.43 (1H, dd, J=5.5, 13.9 Hz), 2.51-2.58 (1H, m),2.56 (1H, dd, J=3.7, 13.9 Hz), 2.65 (1H, dd, J=2.2, 8.1 Hz), 2.72 (1H,dt, J=2.2, 5.9 Hz), 3.51 (1H, dt, J=4.4, 8.4 Hz), 3.75-3.80 (1H, m),4.91 (1H, dd, J=8.8, 10.6 Hz), 5.00 (1H, d, J=10.6 Hz), 5.42 (1H, dd,J=9.2, 15.0 Hz), 5.49 (1H, dd, J=9.2, 15.0 Hz), 5.65 (1H, dd, J=8.4,15.0 Hz), 6.08 (1H, d, J=10.6 Hz), 6.32 (1H, dd, J=10.6, 15.0 Hz)

Example 5 Physicochemical Properties of 6-Deoxy 11107BI

Physicochemical properties of 6-deoxy 11107BI are shown below. 6-deoxy11107BI was determined to have a structure represented by the followingformula.

1. Molecular weight: 504, ESI-MS 527 (M+Na)⁺, ESI-MS 503 (M−H)⁻

2.

¹H-NMR spectrum (CD₃OD, 400 MHz): δ ppm (integration, multiplicity,coupling constant J (Hz)): 0.86 (3H, d, J=6.6 Hz), 0.92 (3H, t, J=7.3Hz), 0.97 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz), 1.01 (3H, d, J=7.0Hz), 1.25-1.35 (3H, m), 1.53-1.61 (3H, m), 1.72 (3H, d, J=0.7 Hz),1.89-1.95 (1H, m), 2.00 (3H, s), 2.02-2.05 (2H, m), 2.10 (1H, dd, J=7.0,14.3 Hz), 2.27-2.31 (1H, m), 2.43 (1H, dd, J=5.1, 13.9 Hz), 2.50-2.56(1H, m), 2.56 (1H, dd, J=3.3, 13.9 Hz), 3.18 (1H, dt, J=3.3, 8.8 Hz),3.75-3.80 (1H, m), 4.91 (1H, covered with H₂O), 5.00 (1H, d, J=10.6 Hz),5.32 (1H, dd, J=7.3, 15.4 Hz), 5.38 (1H, dd, J=6.2, 15.4 Hz), 5.41 (1H,dd, J=9.2, 15.0 Hz), 5.49 (1H, dd, J=9.2, 15.4 Hz), 5.64 (1H, dd, J=7.7,15.0 Hz), 6.06 (1H, d, J=11.0 Hz), 6.21 (1H, dd, J=9.9, 15.0 Hz)

Example 6 Acquisition of a Strain for Converting 6-Deoxy 11107B Into6-Deoxy 11107D

A part of a slant culture medium (yeast-malt agar culture medium) of astrain separated from the soil was inoculated into a 250 mL-volumeconical flask containing 20 mL of a seed culture medium (soluble starch:2.4%, glucose: 0.1%, soybean meal (Esusan meat, manufactured byAjinomoto Co., Inc.): 0.5%, beef extract (manufactured by Diffco Co.):0.3%, yeast extract (manufactured by Diffco Co.): 0.5%, tryptone peptone(manufactured by Diffco Co.): 0.5%, and calcium carbonate: 0.4%), andthe cells were cultured on a shaking culture apparatus at 28° C. forthree days to obtain a seed culture solution. Further, 0.6 mL of theseed culture solution was inoculated into a 500 mL-volume conical flaskcontaining 60 mL of a production culture medium (potato starch: 2%,glucose: 2%, soybean meal (Esusan meat, manufactured by Ajinomoto Co.,Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0.25%, calciumcarbonate: 0.32%, copper sulfate: 0.0005%, manganese chloride: 0.0005%and zinc sulfate: 0.0005%; pH 7.4), and the cells were cultured on ashaking culture apparatus at 28° C. for four days. 2 mL each of theresulting culture solution was dispensed to a 15 mL-volume test tube,and centrifuged at 3,000 rpm for five minutes to harvest the cells. Thecells were suspended in 2 mL of a 50 mM phosphate buffer solution (pH6.0). Next, 6-deoxy 11107B as a substrate was prepared as a 5 mg/mLsolution in dimethylsulfoxide, and 0.04 mL each of the solution wasadded to the suspension. After the addition, the mixture was shaken at28° C. for 23 hours to conduct hydroxylation reaction. After thereaction, an HPLC analysis was conducted to select two strains in whichthe peak of 6-deoxy 11107D appears, strain A-1544 and strain A-1545.These strains were deposited with International Patent OrganismDepositary, National Institute of Advanced Industrial Science andTechnology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566,Japan as FERM P-18943 and FERM P-18944, respectively, on Jul. 23, 2002,and were transferred to International Patent Organism Depositary (IPOD),National Institute of Advanced Industrial Science and Technology inCentral 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan under theinternational depositary numbers FERM BP-8446 and FERM BP-8447,respectively, on Jul. 30, 2003.

The retention time of the above-described compounds when analyzed underthe following analytical HPLC conditions are shown below. AnalyticalHPLC conditions (b)

-   Column: CAPCELL PAK C18 SG120, diameter: 4.6 mm, length: 250 mm    (manufactured by Shiseido Co., Ltd.)-   Temperature: 40° C.-   Flow rate: 1 mL/min-   Detection: 240 nm-   Eluate: Acetonitrile/water (50:50, v/v), isocratic-   Retention time:-   6-deoxy 11107B: 27.2 minutes-   6-deoxy 11107D: 8.2 minutes

Example 7 Culture of A-1544

A part of a slant culture medium (yeast-malt agar culture medium) ofA-1544 was inoculated into a 250 mL-volume conical flask containing 25mL of a seed culture medium (potato starch: 2%, glucose: 2%, soybeanmeal (Esusan meat, manufactured by Ajinomoto Co., Inc.): 2%, yeastextract: 0.5%, sodium chloride: 0.25%, calcium carbonate: 0.32%, coppersulfate: 0.0005%, manganese chloride: 0.0005% and zinc sulfate: 0.0005%;pH 7.4), and the cells were cultured on a shaking culture apparatus at28° C. for three days to obtain a seed culture solution. 0.75 mL each ofthis culture solution was dispensed to a 2 mL-volume serum tube(manufactured by Sumitomo Bakelite Co., Ltd.), and the same amount of40% glycerol aqueous solution was added to the solution. The mixture wasstirred and then frozen at −70° C. to prepare frozen seed culture. Thisfrozen seed culture was melted. The 0.25 mL of the culture wasinoculated into a 250 mL-volume conical flask containing 25 mL of a seedculture medium (potato starch: 2%, glucose: 2%, soybean meal (Esusanmeat, manufactured by Ajinomoto Co., Inc.): 2%, yeast extract: 0.5%,sodium chloride: 0.25%, calcium carbonate: 0.32%, copper sulfate:0.0005%, manganese chloride: 0.0005% and zinc sulfate: 0.0005%; pH 7.4),and the cells were cultured on a shaking culture apparatus at 28° C. fortwo days to obtain a seed culture solution. Further, 0.25 mL of the seedculture solution was inoculated into a 250 mL-volume conical flaskcontaining 25 mL of a production culture medium (potato starch: 2%,glucose: 2%, soybean meal (S-San meat, manufactured by Ajinomoto Co.,Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0.25%, calciumcarbonate: 0.32%, copper sulfate: 0.0005%, manganese chloride: 0.0005%and zinc sulfate: 0.0005%; pH 7.4), and the cells were cultured on ashaking culture apparatus at 25° C. for four days.

Example 8 Production of 6-Deoxy 11107D by Bioconversion Reaction

Each of the strain A-1544 culture solutions obtained by the method ofExample 7 (30 conical flasks with a volume of 25 mL/250 mL each) wascentrifuged at 3,000 rpm for 10 minutes to harvest the cells. The cellswere suspended in 25 mL of a 50 mM phosphate buffer solution (pH 6.0).Next, 6-deoxy 11107B as a substrate was prepared as a 50 mg/mL solutionin dimethylsulfoxide, and 0.25 mL each of the solution was added to thesuspension. After the addition, the mixture was shaken at 28° C. for 22hours to conduct hydroxylation reaction. After the reaction, thereaction product was centrifuged at 5,000 rpm for 20 minutes to separatethe product into a filtrate and cells. The supernatant liquid wasextracted with ethyl acetate (750 mL). The cells were extracted withacetone (500 mL), and the extract was filtrated to obtain an acetoneextract. Acetone of the acetone extract was removed by distillationunder reduced pressure, and then the distilled product was extractedwith ethyl acetate (750 mL). The respective ethyl acetate-layer waswashed with water, and dried by dehydration with anhydrous sodiumsulfate. Then, these layers were concentrated together under reducedpressure to obtain 365 mg of a crude active fraction. This crude activefraction was subjected to silica gel column chromatography (Kiesel gel60, 35 g), washed with toluene (70 mL), and then eluted with a mixedsolution of toluene with acetone (4:1; v/v)(500 mL) and a mixed solutionof toluene with acetone (2:1; v/v)(300 mL) to obtain 139 mg of a crudeactive fraction containing 6-deoxy 11107D and 6-deoxy 11107BP, 78 mg ofa crude active fraction containing 6-deoxy 11107AV and 78 mg of a crudeactive fraction containing 6-deoxy 11107D 20-OH and 6-deoxy 11107F. Theresulting crude active fraction containing 6-deoxy 11107D and 6-deoxy11107BP was subjected to preparative high-performance liquidchromatography (HPLC) under the preparative conditions (B1) describedbelow to obtain a 6-deoxy 11107D fraction and 6-deoxy 11107BP fractioneluted. Then, the solvent was removed by distillation to obtain 6-deoxy11107D (67.0 mg) and 6-deoxy 11107BP (8.1 mg). Similarly, the crudeactive fraction containing 6-deoxy 11107AV and the crude active fractioncontaining 6-deoxy 11107D 20-OH and 6-deoxy 11107F were fractionatedusing HPLC under the preparative conditions (A1) described above and thepreparative conditions (B2) described below, respectively. Then, thesolvents were removed by distillation to obtain 6-deoxy 11107AV (9.3mg), 6-deoxy 11107D 20-OH (19.9 mg), and 6-deoxy 11107F (22.1 mg).

Example 9 Culture of Strain A-1545

A part of a slant culture medium (yeast-malt agar culture medium) ofA-1545 was inoculated into a 250 mL-volume conical flask containing 25mL of a seed culture medium (potato starch: 2%, glucose: 2%, soybeanmeal (Esusan meat, manufactured by Ajinomoto Co., Inc.): 2%, yeastextract: 0.5%, sodium chloride: 0.25%, calcium carbonate: 0.32%, coppersulfate: 0.0005%, manganese chloride: 0.0005% and zinc sulfate: 0.0005%;pH 7.4), and the cells were cultured on a shaking culture apparatus at28° C. for three days to obtain a seed culture solution. 0.75 mL each ofthis culture solution was dispensed to a 2 mL-volume serum tube(manufactured by Sumitomo Bakelite Co., Ltd.), and the same amount of40% glycerol aqueous solution was added to the solution. The mixture wasstirred and then frozen at −70° C. to prepare frozen seed culture. Thisfrozen seed culture was melted, and 0.25 mL of the culture wasinoculated into a 250 mL-volume conical flask containing 25 mL of a seedculture medium (potato starch: 2%, glucose: 2%, soybean meal (Esusanmeat, manufactured by Ajinomoto Co., Inc.): 2%, yeast extract: 0.5%,sodium chloride: 0.25%, calcium carbonate: 0.32%, copper sulfate:0.0005%, manganese chloride: 0.0005% and zinc sulfate: 0.0005%; pH 7.4),and the cells were cultured on a shaking culture apparatus at 28° C. fortwo days to obtain a seed culture solution. Further, 0.25 mL of the seedculture solution was inoculated into a 250 mL-volume conical flaskcontaining 25 mL of a production culture medium (potato starch: 2%,glucose: 2%, soybean meal (Esusan meat, manufactured by Ajinomoto Co.,Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0.25%, calciumcarbonate: 0.32%, copper sulfate: 0.0005%, manganese chloride: 0.0005%and zinc sulfate: 0.0005%; pH 7.4), and the cells were cultured on ashaking culture apparatus at 25° C. for four days.

Example 10 Production of 6-Deoxy 11107D by Bioconversion Reaction

Each of the strain A-1545 culture solutions obtained by the method ofExample 9 (40 conical flasks with a volume of 25 mL/250 mL each) wascentrifuged at 3,000 rpm for 10 minutes to harvest the cells. The cellswas suspended in 25 mL of a 50 mM phosphate buffer solution (pH 6.0).Next, 6-deoxy 11107B as a substrate was prepared as a 50 mg/mL solutionin dimethylsulfoxide, and 0.25 mL each of the solution was added to thesuspension. After the addition, the mixture was shaken at 28° C. for 22hours to conduct hydroxylation reaction. After the reaction, thereaction product was centrifuged at 5,000 rpm for 20 minutes to separatethe product into a filtrate and cells. The supernatant liquid wasextracted with ethyl acetate (1 L). The cells were extracted withacetone (500 mL), and the extract was filtrated to obtain an acetoneextract. Acetone of the acetone extract was removed by distillationunder reduced pressure, and then the distilled product was extractedwith ethyl acetate (1 L). The respective ethyl acetate layer was washedwith water, and dried by dehydration with anhydrous sodium sulfate.Then, these layers were concentrated together under reduced pressure toobtain 537 mg of a crude active fraction. This crude active fraction wassubjected to silica gel column chromatography (Kiesel gel 60, 50 g),washed with toluene (100 mL), and then eluted with a mixed solution oftoluene with acetone (4:1; v/v)(600 mL) and a mixed solution of toluenewith acetone (2:1; v/v)(600 mL) to obtain 112 mg of a crude activefraction containing 6-deoxy 11107D and 47 mg of a crude active fractioncontaining 6-deoxy 11107D 20-OH, 6-deoxy 11107D 17-OH and 6-deoxy 11107D17-OH (17-position epimer). The resulting crude active fractioncontaining 6-deoxy 11107D was subjected to preparative high-performanceliquid chromatography (HPLC) under the preparative conditions (B1)described below to obtain a 6-deoxy 11107D fraction eluted. Then, thesolvent was removed by distillation to obtain 6-deoxy 11107D (67.2 mg).Similarly, the crude active fraction containing 6-deoxy 11107AV and thecrude active fraction containing 6-deoxy 11107D 20-OH, 6-deoxy 11107D17-OH and 6-deoxy 11107D 17-OH (17-position epimer) were fractionatedusing HPLC under the preparative conditions (A1) described above and thepreparative conditions (B2) described below, respectively. Then, thesolvents were removed by distillation to obtain 6-deoxy 11107AV (5.7mg), 6-deoxy 11107D 20-OH (9.0 mg), 6-deoxy 11107D 17-OH (5.9 mg), and6-deoxy 11107D 17-OH (17-position epimer) (6.4 mg).

Preparative HPLC conditions (B1)

-   Column: CAPCELL PAK C18 UG120, diameter: 30 mm, length: 250 mm    (manufactured by Shiseido Co., Ltd.)-   Flow rate: 20 mL/min-   Detection: 240 nm-   Eluate: Acetonitrile/water (40:60, v/v), isocratic-   Preparative HPLC conditions (B2)-   Column: CAPCELL PAK C18 UG120, diameter: 30 mm, length: 250 mm    (manufactured by Shiseido Co., Ltd.)-   Flow rate: 20 mL/min-   Detection: 240 nm-   Eluate: Acetonitrile/water (35:65, v/v), isocratic

The retention time of the above-described compounds when analyzed underthe following analytical HPLC conditions is shown below. Analytical HPLCconditions (c)

-   Column: CAPCELL PAK C18 SG120, diameter: 4.6 mm, length: 250 mm    (manufactured by Shiseido Co., Ltd.)-   Temperature: 40° C.-   Flow rate: 1 mL/min-   Detection: 240 nm-   Eluate: Acetonitrile/water (45:55, v/v), isocratic-   Retention time:-   6-deoxy 11107D: 12.5 minutes-   Analogue 1 (6-deoxy 11107BP): 11.4 minutes-   Analogue 2 (6-deoxy 11107D 20-OH): 7.3 minutes-   Analogue 3 (6-deoxy 11107F): 4.6 minutes-   Analogue 4 (6-deoxy 11107D 17-OH): 7.8 minutes-   Analogue 5 (6-deoxy 11107D 17-OH): 8.3 minutes-   Analogue 6 (6-deoxy 11107AV): 17.8 minutes

Example 11 Physicochemical Properties of 6-Deoxy 11107D

Physicochemical properties of 6-deoxy 11107D are shown below. 6-deoxy11107D was determined to have a structure represented by the formula(XVII′).

1. Molecular weight: 536, ESI MS 559 (M+Na)⁺, ESI-MS 535 (M−H)⁻

2. ¹H-NMR spectrum (CD₃OD, 400 MHz): δ ppm (integration, multiplicity,coupling constant J (Hz)): 0.87 (3H, d, J=7.0 Hz), 0.90 (3H, d, J=7.0Hz), 0.94 (3H, t, J=7.3 Hz), 0.97 (3H, d, J-6.6 Hz), 1.21-1.26 (1H, m),1.29-1.37 (3H, m), 1.34 (3H, s), 1.44-1.52 (2H, m), 1.60-1.64 (1H, m),1.65 (1H, dd, J=6.2, 13.9 Hz), 1.77 (3H, d, J=1.1 Hz), 1.86 (1H, dd,J=5.4, 13.9 Hz), 1.89-1.94 (1H, m), 2.00 (3H, s), 2.43 (1H, dd, J=5.5,13.9 Hz), 2.50-2.60 (1H, m), 2.56 (1H, dd, J=3.3, 13.9 Hz), 2.66 (1H,dd, J=2.2, 7.7 Hz), 2.89 (1H, dt, J=2.2, 6.2 Hz), 3.52 (1H, dt, J=4.8,8.4 Hz), 3.75-3.80 (1H, m), 4.90 (1H, covered with H₂O), 5.01 (1H, d,J=10.6 Hz), 5.42 (1H, dd, J=9.2, 15.0 Hz), 5.50 (1H, dd, J=9.2, 15.0Hz), 5.86 (1H, d, J=15.0 Hz), 6.13 (1H, d, J=10.6 Hz), 6.52 (1H, dd,J=11.0, 15.0 Hz)

Example 12 Physicochemical Properties of Analogue 1 (6-Deoxy 11107BP)

Physicochemical properties of an analogue 1 are shown below. Theanalogue 1 was determined to have a structure represented by thefollowing formula.

1. Molecular weight: 550, ESI-MS 573 (M+Na)⁺, ESI-MS 549 (M−H)⁻

2. ¹H-NMR spectrum (CD₃OD, 400 MHz): δ ppm (integration, multiplicity,coupling constant J (Hz)): 0.86 (3H, d, J=7.0 Hz), 0.97 (3H, d, J=6.6Hz), 1.01 (3H, t, J=7.0 Hz), -1.25 (3H, s), 1.29-1.35 (2H, m), 1.34 (3H,s), 1.58-1.65 (2H, m), 1.68 (1H, dd, J=6.2, 13.9 Hz), 1.77 (3H, d, J=1.1Hz), 1.86 (1H, dd, J=5.5, 13.9 Hz), 1.88-1.93 (1H, m), 2.00 (3H, s),2.42 (1H, dd, J=5.1, 14.3 Hz), 2.52-2.58 (1H, m), 2.56 (1H, dd, J=3.3,14.3 Hz), 2.61-2.76 (2H, m), 3.00 (1H, d, J=2.2 Hz), 3.17 (1H, dt,J=2.2, 5.9 Hz), 3.75-3.80 (1H, m), 4.91 (1H, dd, J=9.2, 10.3 Hz), 5.01(1H, d, J=10.6 Hz), 5.42 (1H, dd, J=9.2, 15.0 Hz), 5.50 (1H, dd, J=9.2,15.0 Hz), 5.87 (1H, d, J=15.4 Hz), 6.14 (1H, d, J=11.0 Hz), 6.53 (1H,dd, J=11.0, 15.4 Hz)

Example 13 Physicochemical Properties of Analogue 2 (6-Deoxy 11107D20-OH)

Physicochemical properties of an analogue 2 are shown below. Theanalogue 2 was determined to have a structure represented by thefollowing formula.

1. Molecular weight: 552, ESI-MS 575 (M+Na)⁺, ESI-MS 551 (M−H)⁻

2. ¹H-NMR spectrum (CD₃OD, 400 MHz): δ ppm (integration, multiplicity,coupling constant J (Hz)): 0.87 (3H, d, J=7.0 Hz), 0.97 (3H, d, J=7.0Hz), 1.01 (3H, t, J=7.3 Hz), 1.04 (3H, s), 1.25-1.35 (3H, m), 1.35 (3H,s), 1.55-1.65 (2H, m), 1.69 (1H, dd, J=5.9, 13.9 Hz), 1.72-1.77 (1H, m),1.77 (3H, s), 1.86 (1H, dd, J=5.9, 13.9 Hz), 1.88-1.95 (1H, m), 2.00(3H, s), 2.43 (dd, J=5.4, 13.9 Hz), 2.50-2.60 (1H, m), 2.56 (1H, dd,J=3.3, 13.9 Hz), 2.90 (1H, d, J=2.2 Hz), 3.10 (1H, dt, J=2.2, 5.9 Hz),3.30 (1H, dd, J=2.0, 10.7 Hz), 3.75-3.81 (1H, m), 4.71 (1H, dd, J=9.2,10.3 Hz), 5.01 (1H, d, J=10.6 Hz), 5.42 (1H, dd, J=8.8, 15.0 Hz), 5.50(1H, dd, J=8.9, 15.0 Hz), 5.87 (1H, d, J=15.4 Hz), 6.13 (1H, d, J=11.0Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz)

Example 14 Physicochemical Properties of Analogue 3 (6-Deoxy 11107F)

Physicochemical properties of an analogue 3 are shown below. Theanalogue 3 was determined to have a structure represented by thefollowing formula.

1. Molecular weight: 494, ESI-MS 517 (M+Na)⁺, ESI-MS 493 (M−H)⁻

2. ¹H-NMR spectrum (CD₃OD, 400 MHz): δ ppm (integration, multiplicity,coupling constant J (Hz)): 0.90 (6H, d, J=7.0 Hz), 0.94 (3H, t, J=7.3Hz), 1.07 (3H, d, J=6.6 Hz), 1.21-1.26 (2H, m), 1.27-1.30 (1H, m), 1.34(3H, s), 1.43-1.54 (2H, m), 1.57-1.68 (3H, m), 1.78 (3H, s), 1.87 (1H,dd, J=5.1, 13.9 Hz), 2.42 (1H, dd, J=5.5, 14.3 Hz), 2.52-2.58 (1H, m),2.57 (1H, dd, J=3.3, 14.3 Hz), 2.67 (1H, dd, J=2.2, 8.1 Hz), 2.89 (1H,dt, J=2.2, 5.9 Hz), 3.52 (1H, dt, J=4.8, 9.2 Hz), 3.57 (1H, dd, J=9.5,9.9 Hz), 3.73-3.79 (1H, m), 5.02 (1H, d, J=10.6 Hz), 5.31 (1H, dd,J=9.5, 15.0 Hz), 5.47 (1H, dd, J=9.2, 15.0 Hz), 5.86 (1H, d, J=15.0 Hz),6.12 (1H, d, J=11.0 Hz), 6.53 (1H, dd, J=11.0, 15.0 Hz)

Example 15 Physicochemical Properties of Analogue 4 (6-Deoxy 11107D17-OH)

Physicochemical properties of an analogue 4 are shown below. Theanalogue 4 was determined to have a structure represented by thefollowing formula.

1. Molecular weight: 552, ESI-MS 575 (M+Na)⁺, ESI-MS 551 (M−H)⁻

2. ¹H-NMR spectrum (CD₃OD, 400 MHz): δ ppm (integration, multiplicity,coupling constant J (Hz)): 0.87 (3H, d, J=6.2 Hz), 0.88 (3H, d, J=7.0Hz), 0.94 (3H, t, J=7.3 Hz), 0.97 (3H, d, J=7.0 Hz), 1.25-1.25 (3H, m),1.32 (3H, s), 1.44-1.55 (2H, m), 1.57-1.67 (2H, m), 1.77 (3H, s),1.88-1.95 (1H, m), 2.00 (3H, s), 2.43 (1H, dd, J=5.5, 13.9 Hz), 2.57(1H, dd, J=3.3, 13.9 Hz), 2.51-2.61 (1H, m), 2.84 (1H, dd, J=2.2, 7.7Hz), 2.92 (1H, dd, J=2.2, 6.6 Hz), 3.12 (1H, d, J=6.6 Hz), 3.54 (1H, dt,J=4.8, 7.7 Hz), 3.74-3.81 (1H, m), 4.91 (1H, dd, J=9.1, 10.3 Hz), 5.01(1H, d, J=10.6 Hz), 5.42 (1H, dd, J=9.1, 14.7 Hz), 5.50 (1H, dd, J=8.8,14.7 Hz), 5.92 (1H, d, J=15.0 Hz), 6.14 (1H, d, J=11.0 Hz), 6.58 (1H,dd, J=11.0, 15.0 Hz)

Example 16 Physicochemical Properties of Analogue 5 (6-Deoxy 11107D17-OH)

Physicochemical properties of an analogue 5 are shown below. Theanalogue 5 was determined to have a structure represented by thefollowing formula. This compound is a stereoisomer of the hydroxyl groupat the 17-position of the analogue 4.

1. Molecular weight: 552, ESI-MS 575 (M+Na)⁺, ESI-MS 551 (M−)⁻

2. ¹H-NMR spectrum (CD₃OD, 400 MHz): δ ppm (integration, multiplicity,coupling constant J (Hz)): 0.87 (3H, d, J=6.6 Hz), 0.89 (3H, d, J=7.0Hz), 0.94 (3H, t, J=7.3 Hz), 0.97 (3H, d, J=7.0 Hz), 1.20-1.40 (3H, m),1.34 (3H, s), 1.43-1.67 (4H, m), 1.77 (3H, s), 1.87-1.96 (1H, m), 2.00(3H, s), 2.43 (1H, dd, J=5.1, 13.9 Hz), 2.57 (1H, dd, J=3.3, 13.9 Hz),2.54-2.55 (1H, m), 2.93-2.96 (2H, m), 3.44 (1H, d, J=3.3 Hz), 3.52 (1H,dt, J=4.4, 8.4 Hz), 3.74-3.81 (1H, m), 4.91 (1H, covered with H₂O), 5.01(1H, d, J=10.6 Hz), 5.42 (1H, dd, J=8.8, 15.0 Hz), 5.50 (1H, dd, J=9.2,15.0 Hz), 5.93 (1H, d, J=15.4 Hz), 6.13 (1H, d, J=11.0 Hz), 6.59 (1H,dd, J=11.0, 15.9 Hz)

Example 17 Physicochemical Properties of Analogue 6 (6-Deoxy 11107AV)

Physicochemical properties of an analogue 6 are shown below. Theanalogue 6 was determined to have a structure represented by thefollowing formula.

1. Molecular weight: 534, ESI-MS 557 (M+Na)⁺, ESI-MS 533 (M−)⁻

2. ¹H-NMR spectrum (CD₃OD, 400 MHz): δ ppm (integration, multiplicity,coupling constant J (Hz)): 0.87 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=7.7Hz), 0.98 (3H, t, J=7.3 Hz), 1.07 (3H, d, J=7.0 Hz), 1.28-1.32 (2H, m),1.33 (3H, s), 1.58-1.64 (2H, m), 1.63 (1H, dd, J=6.6, 14.3 Hz), 1.77(3H, d, J=1.1 Hz), 1.88-1.94 (1H, m), 1.89 (1H, dd, J=5.1, 14.3 Hz),2.28-2.35 (1H, m), 2.42 (1H, dd, J=5.5, 14.3 Hz), 2.52-2.63 (4H, m),2.75 (1H, dd, J=2.2, 8.4 Hz), 2.91 (1H, dt, J=2.2, 6.6 Hz), 3.75-3.80(1H, m), 4.91 (1H, dd, J=8.8, 10.3 Hz), 5.01 (1H, d, J=10.6 Hz), 5.42(1H, dd, J=8.8, 15.0 Hz), 5.50 (1H, dd, J=9.2, 15.0 Hz), 5.86 (1H, d,J=15.4 Hz), 6.13 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz)

Example 18(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 18)

Example 18-1 Step (1)(8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide

(8E,12E,14E)-7-acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(6-deoxy 11107D) (129 mg, 240 μmol) was dissolved in methylene chloride(2 mL). Ethyl vinyl ether (1.4 mL, 14.4 mmol) and pyridiniump-toluenesulfonate (19.9 mg, 79.2 μmol) were added to the reactionmixture at room temperature, and the reaction mixture was stirred at thesame temperature for 4.5 hours. This reaction mixture was diluted withethyl acetate (30 mL), and the organic layer was washed with purifiedwater (10 mL) and brine (10 mL). The resulting organic layer was driedover anhydrous sodium sulfate, and then filtered. The filtrate wasconcentrated under reduced pressure to obtain the title compound as acrude product (188 mg).

ESI-MS m/z 775 (M+Na)⁺.

Example 18-2 Step (2)(8E,12E,14E)-3,16,21-tris(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide

(8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(186 mg) as the crude product was dissolved in methanol (2 mL).Potassium carbonate (75.0 mg, 543 μmol) was added to the reactionmixture, and the reaction mixture was stirred at room temperature forthree hours. This reaction solution was diluted with ethyl acetate (50mL), and the organic layer was washed with brine (10 mL) twice. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting concentrate was purified by silica gelcolumn chromatography (Merck Silica gel 60, 63 to 200 μm; hexane:ethylacetate=3:1→2:1) to obtain the title compound (131 mg, 185 μmol, 78.6%,2 steps) as a colorless oil.

ESI-MS m/z 733 (M+Na)⁺.

Example 18-3 Step (3)(8E,12E,14E)-3,16,21-tris(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxytricosa-8,12,14-trien-11-olide

(8E,12E,14E)-3,16,21-tris(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(129 mg, 182 μmol) was dissolved in methylene chloride (1 mL).Triethylamine (127 μL, 911 μmol) and 4-dimethylaminopyridine (67.0 mg,548 μmol) were added to the reaction mixture, and the reaction mixturewas stirred at room temperature for 30 minutes. A solution of4-nitrophenyl chloroformate (112 mg, 556 μmol) in methylene chloride (1mL) was added dropwise to this reaction mixture and the reaction mixturewas stirred at room temperature for 3.5 hours. The reaction mixture wasdiluted with ethyl acetate (30 mL), and the organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate (10 mL)and purified water (10 mL) twice, and with brine (10 mL). The resultingorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting concentrate was purified by silica gelcolumn chromatography (Merck Silica gel 60, 63 to 200 μm; hexane:ethylacetate=5:1→4:1) to obtain the title compound (137 mg, 156 μmol, 85.8%)as a colorless oil.

ESI-MS m/z 898 (M+Na)⁺.

Example 18-4 Step (4)(8E,12E,14E)-3,16,21-tris-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide

(8E,12E,14E)-3,16,21-tris(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxytricosa-8,12,14-trien-11-olide(26.6 mg, 30.4 μmol) was dissolved in tetrahydrofuran (0.5 mL). Asolution of 1-methyl piperazine (4.4 μL, 49 μmol) in tetrahydrofuran(0.5 mL) was added to the reaction mixture and the reaction mixture wasstirred at room temperature for 2.5 hours. This reaction solution wasconcentrated, and the concentrate was purified by silica gel columnchromatography (Fuji Silysia NH Silica gel, 100 μm; hexane:ethylacetate=1:1) to obtain the title compound (25.1 mg, 30.0 μmol, 98.7%) asa colorless oil.

ESI-MS m/z 837 (M+H)⁺.

Example 18-5 Step (5)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 18)

(8E,12E,14E)-3,16,21-tris-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(25.1 mg, 30.0 limol) was dissolved in a 1:1 mixed solution oftetrahydrofuran and 2-methyl-1-propanol (1 mL). Pyridiniump-toluenesulfonate (23.7 mg, 94.3 μmol) was added to the reactionmixture at room temperature. The reaction mixture was stirred at thesame temperature for 24.5 hours, and then pyridinium p-toluenesulfonate(8.7 mg, 34.6 μmol) was further added to the reaction mixture. Thereaction mixture was stirred for 4.5 hours. The reaction mixture wasdiluted with ethyl acetate (30 mL), and the organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate (6 mL) andpurified water (6 mL) twice, and with brine (6 mL). The resultingorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting concentrate was purified by thin-layerchromatography (Fuji Silysia NH Silica gel plate;chloroform:methanol=40:1) to obtain the title compound (12.2 mg, 19.6μmol, 65.3%) as a colorless oil.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.0 Hz), 0.89(3H, d, J=6.6 Hz), 0.93 (3H, t, J=7.3 Hz), 0.99 (3H, d, J=6.6 Hz),1.19-1.37 (3H, m), 1.33 (3H, s), 1.40-1.65 (4H, m), 1.65 (1H, dd, J=5.5,14.3 Hz), 1.77 (3H, d, J=0.7 Hz), 1.86 (1H, dd, J=5.5, 14.3 Hz),1.89-1.97 (1H, m), 2.29 (3H, s), 2.35-2.45 (5H, m), 2.53-2.60 (1H, m),2.56 (1H, dd, J=3.7, 13.9 Hz), 2.66 (1H, dd, J=2.2, 8.1 Hz), 2.88 (1H,dt, J=2.2, 5.5 Hz), 3.42-3.54 (5H, m), 3.74-3.81 (1H, m), 4.79 (1H, dd,J=9.2, 9.2 Hz), 5.01 (1H, d, J=10.6 Hz), 5.44 (1H, dd, J=8.8, 15.0 Hz),5.50 (1H, dd, J=9.2, 15.0 Hz), 5.86 (1H, d, J=15.0 Hz), 6.12 (1H, d,J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 621 (M+H)⁺.

Example 19(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 19)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.0 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 0.98-1.03 (3H, m), 1.20-1.68(8H, m), 1.33 (3H, s), 1.77 (3H, s), 1.83-1.98 (4H, m), 2.34 (3H, s),2.42 (1H, dd, J=5.5, 13.9 Hz), 2.50-2.66 (6H, m), 2.66 (1H, dd, J=2.2,7.7 Hz), 2.89 (1H, dd, J=2.2, 6.2 Hz), 3.44-3.59 (5H, m), 3.74-3.80 (1H,m), 4.80 (1H, dd, J=9.2, 9.2 Hz), 5.02 (1H, d, J=10.6 Hz), 5.44 (1H, dd,J=9.2, 15.0 Hz), 5.50 (1H, dd, J=9.2, 15.0 Hz), 5.86 (1H, d, J=15.0 Hz),6.12 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 635(M+H)⁺.

Example 20(8E,12E,14E)-7-(N-(2-(N′,N′-diethylamino)ethyl-N-methyl)carbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 20)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=8.1 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 0.98-1.11 (9H, m), 1.19-1.68(8H, m), 1.33 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J=5.5, 14.3 Hz),1.88-1.98 (1H, m), 2.42 (1H, dd, J=5.5, 14.3 Hz), 2.51-2.63 (8H, m),2.66 (1H, dd, J=2.2, 8.1 Hz), 2.87-2.95 (4H, m), 3.30-3.39 (2H, m), 3.52(1H, dt, J=4.4, 8.8 Hz), 3.74-3.82 (1H, m), 4.80 (1H, dd, J=9.2, 9.2Hz), 5.01 (1H, d, J=10.6 Hz), 5.44 (1H, dd, J=9.2, 15.0 Hz), 5.50 (1H,dd, J=9.2, 15.0 Hz), 5.86 (1H, d, J=15.4 Hz), 6.12 (1H, d, J=11.0 Hz),6.52 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 651 (M+H)⁺.

Example 21(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 21)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.0 Hz), 0.89(3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 0.99 (3H, d, J=6.6 Hz),1.19-1.67 (16H, m), 1.33 (3H, s), 1.77 (3H, s), 1.82-1.97 (4H, m), 2.42(1H, dd, J=5.5, 14.3 Hz), 2.42-2.61 (7H, m), 2.66 (1H, dd, J=2.2, 8.1Hz), 2.69-2.86 (2H, m), 2.88 (1H, dt, J=2.2, 5.9 Hz), 3.52 (1H, dt,J=4.8, 8.4 Hz), 3.73-3.81 (1H, m), 4.12-4.22 (2H, m), 4.77 (1H, dd,J=9.2, 9.2 Hz), 5.01 (1H, d, J=10.6 Hz), 5.43 (1H, dd, J=9.2, 15.0 Hz),5.49 (1H, dd, J=9.2, 15.0 Hz), 5.86 (1H, d, J=15.0 Hz), 6.12 (1H, d,J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 689 (M+H)⁺.

Example 22(8E,12E,14E)-7-(N-(2-(N′,N′-diethylamino)ethyl)carbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 22)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.3 Hz), 0.89(3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 0.99 (3H, d, J=7.0 Hz), 1.05(6H, t, J=7.0 Hz), 1.19-1.65 (7H, m), 1.33 (3H, s), 1.65 (1H, dd, J=5.5,13.9 Hz), 1.76 (3H, s), 1.80-1.90 (1H, m), 1.86 (1H, dd, J=5.5, 13.9Hz), 2.42 (1H, dd, J=5.1, 13.9 Hz), 2.51-2.59 (4H, m), 2.58 (4H, q,J=7.0 Hz), 2.66 (1H, dd, J=2.2, 7.7 Hz), 2.89 (1H, dt, J=2.2, 5.5 Hz),3.15-3.20 (2H, m), 3.52 (1H, dt, J=4.4, 8.4 Hz), 3.72-3.80 (1H, m), 4.74(1H, dd, J=9.5, 9.5 Hz), 5.01 (1H, d, J=10.6 Hz), 5.41 (1H, dd, J=9.2,15.0 Hz), 5.48 (1H, dd, J=9.5, 15.0 Hz), 5.86 (1H, d, J=15.4 Hz), 6.12(1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 637(M+H)⁺.

Example 23(8E,12E,14E)-7-((4-(2,2-dimethylpropyl)piperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 23)

Example 23-1 Step (1)(8E,12E,14E)-7-acetoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide

A solution of(8E,12E,14E)-7-acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(54 mg, 0.1 mmol), 4-dimethylaminopyridine (124 mg, 1 mmol), andtriethylamine (102 mg, 1 mmol) in methylene chloride (2.5 mL) was cooledto 5° C. A solution of triethylsilyl chloride (152 mg, 1 mmol) inmethylene chloride (0.5 mL) was added dropwise to the reaction mixture,and then the reaction mixture was stirred at room temperature overnight.The reaction mixture was diluted with ethyl acetate, and then theorganic layer was washed with water. The resulting organic layer wasdried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (Kanto silica gel 60N, 40 to 50 μm; ethylacetate-hexane, 1:19→1:14) to obtain the title compound (77.1 mg, 88%)as a colorless oil.

ESI-MS m/z 901 (M+Na)⁺.

Example 23-2 Step (2)(8E,12E,14E)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide

(8E,12E,14E)-7-acetoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(77 mg, 0.0875 mmol) was dissolved in methanol (2 mL). Potassiumcarbonate (36.5 mg, 0.262 mmol) and methanol (1 mL) were added to thismethanolic solution, and the reaction mixture was stirred at roomtemperature for four hours. The reaction mixture was diluted with ethylacetate, and then the organic layer was washed with brine. The organiclayer was dried with anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (Kanto silica gel 60N, 40 to 50 ptm;ethyl acetate-hexane, 1:9→1:6→1:4→1:3) to obtain the title compound(38.6 mg, 50%) as a colorless oil.

ESI-MS m/z 859 (M+Na)⁺.

Example 23-3 Step (3)(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide

A solution of(8E,12E,14E)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(38.6 mg, 0.046 mmol), 4-dimethylaminopyridine (26 mg, 0.207 mmol) andtriethylamine (28 mg, 0.276 mmol) in methylene chloride (2 mL) wascooled to 5° C. A solution of 4-nitrophenyl chloroformate (29 mg, 0.138mmol) in methylene chloride (1 mL) was added to the reaction mixture,and the reaction mixture was stirred at 5° C. for one hour. The reactionmixture was diluted with ethyl acetate, and then the organic layer waswashed with an aqueous solution of sodium hydrogencarbonate. The organiclayer was sequentially washed with an aqueous solution of ammoniumchloride, an aqueous solution of sodium hydrogencarbonate and water,dried with anhydrous magnesium sulfate, and filtered. Then, the filtratewas concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (Kanto silica gel 60N, 40to 50 μm; ethyl acetate-hexane, 1:14) to obtain the title compound (46.1mg, 100%) as a yellow pale oil.

ESI-MS m/z 1024 (M+Na)⁺.

Example 23-4 Step (4)(8E,12E,14E)-7-((4-(2,2-dimethylpropyl)piperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide

A solution of 1-(2,2-dimethylpropyl)piperazine ditrifluoroacetate (12mg, 20 μmol) and triethylamine (10 mg, 0.1 mmol) in tetrahydrofuran (0.7mL) was added dropwise to a solution of(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(10 mg, 10 μmol) in tetrahydrofuran (0.5 mL), and the reaction mixturewas stirred at room temperature for three hours. The reaction mixturewas diluted with ethyl acetate, and then the organic layer was washedwith an aqueous solution of sodium hydrogencarbonate. The organic layerwas dried over anhydrous magnesium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by thin-layerchromatography (Merck, Art 1.05628; ethyl acetate-hexane, 1:6) to obtainthe title compound (9.7 mg, 95%) as a colorless oil.

ESI-MS m/z 1019 (M+H)⁺.

Example 23-5 Step (5)(8E,12E,14E)-7-((4-(2,2-dimethylpropyl)piperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 23)

A solution of(8E,12E,14E)-7-((4-(2,2-dimethylpropyl)piperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(9.7 mg, 9.5 μmol) in tetrahydrofuran (1 mL) was cooled to 5° C.Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 31 μL,31 μmol) was added dropwise to the reaction mixture, and the reactionmixture was stirred at room temperature for two hours. The reactionmixture was diluted with ethyl acetate, and then the organic layer waswashed with an aqueous solution of sodium hydrogencarbonate. The organiclayer was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby thin-layer chromatography (Fuji Silysia NH Silica gel plate;methanol-methylene chloride, 1:49) to obtain the title compound (6.3 mg,98%) as a colorless oil.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.85-0.92 (15H, m), 0.94 (3H,t, J=7.6 Hz), 0.99 (3H, d, J=6.8 Hz), 1.19-1.69 (11H, m), 1.77 (3H, d,J=0.8 Hz), 1.86 (1H, dd, J=5.2, 14.0 Hz), 1.87-1.97 (1H, m), 2.09 (2H,s), 2.38-2.61 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt,J=2.0, 6.0 Hz), 3.34-3.52 (4H, m), 3.52 (1H, td, J=4.4, 7.6 Hz),3.74-3.81 (1H, m), 4.75-4.82 (1H, m), 5.01 (1H, d, J=10.8 Hz), 5.43 (1H,dd, J=8.8, 14.8 Hz), 5.50 (1H, dd, J=9.2, 14.8 Hz), 5.86 (1H, d, J=15.2Hz), 6.12 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z677 (M+H)⁺.

Example 24(8E,12E,14E)-7-((4-ethylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 24)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.00 (3H, d, J=6.8 Hz), 1.11(3H, t, J=7.2 Hz), 1.19-1.70 (11H, m), 1.77 (3H, d, J=0.8 Hz), 1.86 (1H,dd, J=5.6, 14.0 Hz), 1.88-1.99 (1H, m), 2.38-2.49 (7H, m), 2.51-2.61(2H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz),3.40-3.57 (5H, m), 3.74-3.82 (1H, m), 4.76-4.83 (1H, m), 5.01 (1H, d,J=10.8 Hz), 5.44 (1H, dd, J=8.8, 15.2 Hz), 5.51 (1H, dd, J=9.2, 14.8Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.52 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 635 (M+H)⁺.

Example 25(8E,12E,14E)-7-((4-(N,N-dimethylamino)piperidin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 25)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.00 (3H, d, J=6.8 Hz),1.19-1.70 (13H, m), 1.77 (3H, d, J=0.8 Hz), 1.82-1.99 (4H, m), 2.28 (6H,s), 2.32-2.46 (2H, m), 2.50-2.62 (2H, m), 2.67 (1H, dd, J=2.4, 7.6 Hz),2.68-2.88 (2H, m), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.52 (1H, td, J=4.4,8.0 Hz), 3.74-3.82 (1H, m), 4.11-4.21 (2H, m), 4.75-4.82 (1H, m), 5.02(1H, d, J=10.8 Hz), 5.44 (1H, dd, J=8.8, 15.2 Hz), 5.50 (1H, dd, J=9.2,14.8 Hz), 5.86 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.52 (1H,dd, J=10.8, 15.2 Hz); ESI-MS m/z 649 (M+H)⁺.

Example 26(8E,12E,14E)-7-(N-(3-(N′,N′-dimethylamino)propyl)carbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 26)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.8 Hz), 0.89(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.4 Hz), 1.00 (3H, d, J=6.4 Hz),1.19-1.71 (10H, m), 1.34 (3H, s), 1.77 (3H, s), 1.82-1.90 (2H, m), 2.24(6H, s), 2.34 (2H, t, J=7.6 Hz), 2.42 (1H, dd, J=5.4, 14.2 Hz),2.50-2.60 (2H, m), 2.66 (1H, dd, J=2.2, 7.8 Hz), 2.89 (1H, dt, J=2.2,5.6 Hz), 3.10 (2H, t, J=6.8 Hz), 3.48-3.55 (1H, m), 3.72-3.82 (1H, m),4.74 (1H, dd, J=9.4, 9.4 Hz), 5.02 (1H, d, J=10.8 Hz), 5.37-5.53 (2H,m), 5.86 (1H, d, J=15.2 Hz), 6.12 (1H, d, J=10.8 Hz), 6.52 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 623 (M+H)⁺.

Example 27(8E,12E,14E)-7-(N-(3-(N′,N′-dimethylamino)propyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 27)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=7.2 Hz), 0.89(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.4 Hz), 1.01 (3H, d, J=6.4 Hz),1.19-1.79 (10H, m), 1.34 (3H, s), 1.77 (3H, s), 1.82-1.98 (2H, m), 2.26(6H, s), 2.28-2.37 (2H, m), 2.42 (1H, dd, J=5.2, 14.0 Hz), 2.51-2.59(2H, m), 2.66 (1H, dd, J=2.2, 7.8 Hz), 2.83-2.94 (4H, m), 3.22-3.37 (2H,covered with CD₃OD), 3.48-3.55 (1H, m), 3.74-3.82 (1H, m), 4.70-4.96(1H, covered with H₂O), 5.02 (1H, d, J=10.8 Hz), 5.40-5.55 (2H, m), 5.86(1H, d, J=15.6 Hz), 6.12 (1H, d, J=10.8 Hz), 6.52 (1H, dd, J=10.8, 15.2Hz); ESI-MS m/z 637 (M+H)⁺.

Example 28(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 28)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.0 Hz), 0.89(3H, d, J=6.6 Hz), 0.93 (3H, t, J=7.3 Hz), 0.99 (3H, d, J=7.2 Hz),1.19-1.37 (3H, m), 1.33 (3H, s), 1.40-1.54 (2H, m), 1.54-1.68 (3H, m),1.75 (3H, s), 1.82-1.98 (2H, m), 2.35-2.46 (1H, m), 2.48-2.60 (2H, m),2.62-2.68 (1H, m), 2.68-2.80 (4H, m), 2.82-2.92 (1H, m), 3.34-3.54 (5H,m), 3.72-3.82 (1H, m), 4.74-4.92 (1H, covered with H₂O), 5.01 (1H, d,J=10.4 Hz), 5.34-5.54 (2H, m), 5.86 (1H, d, J=15.0 Hz), 6.12 (1H, d,J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 607 (M+H)⁺.

Example 29(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 29)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 40 MHz) δ (ppm): 0.88 (3H, d, J=6.8 Hz), 0.89(3H, d, J=7.2 Hz), 0.93 (3H, t, J=7.6 Hz), 0.99 (3H, d, J=6.8 Hz),1.00-1.04 (1H, m), 1.19-1.68 (11H, m), 1.33 (3H, s), 1.77 (3H, s), 1.86(1H, dd, J=5.2, 14.0 Hz), 1.90-1.98 (1H, m), 2.04-2.16 (2H, m), 2.28(3H, s), 2.42-2.60 (3H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.79 (3H, s),2.84-2.98 (3H, m), 3.52 (1H, dt, J=4.4, 8.4 Hz), 3.72-3.80 (1H, m),3.82-3.98 (1H, m), 4.76-4.92 (1H, covered with H₂O), 5.01 (1H, d, J=10.4Hz), 5.44 (1H, dd, J=9.2, 15.2 Hz), 5.50 (1H, dd, J=9.2, 15.2 Hz), 5.86(1H, d, J=15.2 Hz), 6.12 (1H, d, J=10.8 Hz), 6.52 (1H, dd, J=10.8, 15.2Hz); ESI-MS m/z 649.(M+H)⁺.

Example 30(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(1-methylpiperidin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 30)

Example 30-1 Step (1)(8E,12E,14E)-7-acetoxy-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide

A solution of(8E,12E,14E)-7-acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(177 mg, 0.33 mmol) and imidazole (450 mg, 6.61 mmol) in methylenechloride (6 mL) was cooled to 5° C. A solution of diethylisopropylsilylchloride (272 mg, 1.65 mmol) in methylene chloride (1.5 mL) was addeddropwise to the reaction mixture, and the reaction mixture was stirredat room temperature for two hours. The reaction mixture was diluted withethyl acetate, and then the organic layer was washed with water. Theresulting organic layer was washed with brine dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40 to 100 μm; ethyl acetate-hexane,1:19→1:9→1:6→1:4) to obtain the title compound (242.9 mg, 93%) as acolorless oil.

ESI-MS m/z 815 (M+Na)⁺.

Example 30-2 Step (2)(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-7,16-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide

A 0.2 M guanidine/guanidine nitrate solution (methanol-methylenechloride, 9:1)(3.9 mL, 0.78 mmol) was added to(8E,12E,14E)-7-acetoxy-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(307 mg, 0.3868 mmol), and the reaction mixture was stirred at roomtemperature for 13 hours. The reaction mixture was diluted with ethylacetate, and then the organic layer was washed with an aqueous solutionof ammonium chloride. The resulting organic layer was dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane,1:4) to obtain the title compound (271.5 mg, 93%) as a colorless oil.

ESI-MS m/z 773 (M+Na)⁺.

Example 30-3 Step (3)(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-18,19-epoxytricosa-8,12,14-trien-11-olide

A solution of(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-7,16-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(271 mg, 0.3605 mmol), 4-dimethylaminopyridine (22 mg, 0.18 mmol) andtriethylamine (369 mg, 3.61 mmol) in methylene chloride (5 mL) wascooled to 5° C. A solution of 4-nitrophenyl chloroformate (374 mg, 1.8mmol) in methylene chloride (3 mL) was added dropwise to the solution,and the reaction mixture was stirred at 5 to 10° C. for one hour. Thereaction mixture was diluted with ethyl acetate, and then the organiclayer was washed with an aqueous solution of sodium hydrogencarbonate.The resulting organic layer was washed with water, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9→1:7→1:6)to obtain the title compound (319.6 mg, 97%) as a yellow pale oil.

ESI-MS m/z 938 (M+Na)⁺.

Example 30-4 Step (4)(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-(1-methylpiperidin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide

A solution of 1-(4-methylpiperidin-1-yl)-piperazine (11.7 mg, 63.3 μmol)in tetrahydrofuran (1 mL) and triethylamine (13 mg, 0.127 mmol) wereadded dropwise to a solution of(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(29 mg, 31.6 μmol) in tetrahydrofuran (2 mL), and the reaction mixturewas stirred at room temperature for two hours. The reaction mixture wasdiluted with ethyl acetate, and then the organic layer was washed withan aqueous solution of sodium hydrogencarbonate. The resulting organiclayer was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby thin-layer chromatography (Fuji Silysia NH Silica gel plate; ethylacetate-hexane, 9:1) to obtain the title compound (18.5 mg, 61%) as acolorless oil.

Example 30-5 Step (5)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(1-methylpiperidin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 30)

A solution of(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-(1-methylpiperidin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(18.5 mg, 19.2 μmol) in tetrahydrofuran (2 mL) was cooled to 5° C.Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 42.3 μL,42.3 μmol) was added dropwise to the solution, and the reaction mixturewas stirred at room temperature for four hours. The reaction mixture wasdiluted with ethyl acetate, and then the organic layer was washed withan aqueous solution of sodium hydrogencarbonate. The resulting organiclayer was washed with an aqueous solution of sodium hydrogencarbonate,dried over anhydrous magnesium sulfate, filtered concentrated underreduced pressure. The resulting residue was purified by thin-layerchromatography (Fuji Silysia NH Silica gel plate;methanol-dichloromethane, 1:24) to obtain the title compound (7.6 mg,56%) as a colorless oil.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.00 (3H, d, J=6.8 Hz),1.19-1.69 (13H, m), 1.77 (3H, s), 1.82-1.97 (4H, m), 1.98-2.06 (2H, m),2.25 (3H, s), 2.24-2.32 (1H, m), 2.42 (1H, dd, J=5.2, 14.0 Hz),2.48-2.60 (6H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.87-2.95 (3H, m),3.38-3.55 (5H, m), 3.74-3.81 (1H, m), 4.75-4.82 (1H, m), 5.01 (1H, d,J=10.4 Hz), 5.44 (1H, dd, J=8.8, 14.8 Hz), 5.50 (1H, dd, J=9.2, 14.8Hz), 5.86 (1H, d, J=15.2 Hz), 6.12 (1H, d, J=11.2 Hz), 6.52 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 704 (M+H)⁺.

Example 31(8E,12E,14E)-7-((4-(2-cyanoethyl)piperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 31)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.00 (3H, d, J=6.8 Hz),1.19-1.69 (11H, m), 1.77 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.2, 14.0Hz), 1.88-1.98 (1H, m), 2.38-2.51 (5H, m), 2.52-2.60 (2H, m), 2.61-2.70(5H, m), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.40-3.56 (5H, m), 3.74-3.81 (1H,m), 4.76-4.82 (1H, m), 5.01 (1H, d, J=10.4 Hz), 5.44 (1H, dd, J=8.8,14.8 Hz), 5.50 (1H, dd, J=9.2, 14.8 Hz), 5.86 (1H, d, J=15.2 Hz), 6.12(1H, d, J=10.8 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 660(M+H)⁺, 682 (M+Na)⁺.

Example 32(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 32)

The title compound (colorless oil) was synthesized in the same manner asin Example 30.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 0.97-1.07 (3H, m), 1.19-2.03(25H, m), 2.38-2.69 (10H, m), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.30-3.40(1H, covered with CD₃OD), 3.52 (1H, td, J=4.4, 8.4 Hz), 3.73-3.81 (1H,m), 3.89-3.99 (1H, m), 4.74-4.86 (1H, covered with H₂O), 5.02 (1H, d,J=10.8 Hz), 5.40-5.55 (2H, m), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d,J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 675 (M+H)⁺.

Example 33(8E,12E,14E)-7-((4-(2-(N,N-dimethylamino)ethyl)piperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 33)

The title compound (colorless oil) was synthesized in the same manner asin Example 30.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.00 (3H, d, J=6.8 Hz),1.19-1.69 (11H, m), 1.77 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.2, 14.0Hz), 1.88-1.98 (1H, m), 2.28 (6H, s), 2.39-2.49 (5H, m), 2.49-2.61 (6H,m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz),3.40-3.56 (5H, m), 3.75-3.81 (1H, m), 4.75-4.83 (1H, m), 5.02 (1H, d,J=10.8 Hz), 5.44 (1H, dd, J=8.8, 14.8 Hz), 5.50 (1H, dd, J=9.2, 14.8Hz), 5.86 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 678 (M+H)⁺.

Example 34(8E,12E,14E)-7-((4-benzylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 34)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 0.99 (3H, d, J=7.2 Hz),1.14-1.32 (3H, m), 1.34 (3H, s), 1.36-1.70 (5H, m), 1.77 (3H, d, J=1.2Hz), 1.78-1.96 (2H, m), 2.36-2.48 (5H, m), 2.52-2.60 (2H, m), 2.67 (1H,dd, J=2.4, 10.4 Hz), 2.89 (1H, dt, J=1.6, 5.2 Hz), 3.41-3.58 (7H, m),3.74-3.82 (1H, m), 4.78 (1H, dd, J=9.0, 9.0 Hz), 5.01 (1H, d, J=10.4Hz), 5.44-5.54 (2H, m), 5.87 (1H, d, J=15.2 Hz), 6.12 (1H, d, J=10.8Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz), 7.22-7.38 (5H, m); ESI-MS m/z 697(M+H)⁺.

Example 35(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 35)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=7.2 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 0.99 (3H, d, J=6.8 Hz),1.20-1.32 (3H, m), 1.34 (3H, s), 1.36-1.72 (5H, m), 1.77 (3H, d, J=1.2Hz), 1.80-1.90 (6H, m), 2.04-2.18 (2H, m), 2.26 (3H, s), 2.42 (1H, dd,J=5.6, 14.8 Hz), 2.51-2.59 (2H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz),2.78-2.86 (2H, m), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.35-3.40 (1H, m),3.48-3.54 (1H, m), 3.74-3.80 (1H, m), 4.70-4.79 (1H, m), 5.01 (1H, d,J=10.8 Hz), 5.38-5.42 (2H, m), 5.86 (1H, d, J=15.6 Hz), 6.12 (1H, d,J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 635 (M+H)⁺.

Example 36(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyridin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 36)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.8 Hz), 0.89(3H, d, J=7.2 Hz), 0.93 (3H, t, J=7.2 Hz), 1.01 (3H, d, J=6.8 Hz),1.20-1.32 (3H, m), 1.34 (3H, s), 1.35-1.70 (5H, m), 1.77 (3H, s),1.82-2.01 (2H, m), 2.43 (1H, dd, J=5.2, 14.0 Hz), 2.51-2.62 (2H, m),2.66 (1H, dd, J=2.0, 8.0 Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.38-3.48(4H, m), 3.49-3.55 (1H, m), 3.56-3.66 (4H, m), 3.74-3.82 (1H, m),4.80-4.92 (1H, covered with H₂O), 5.02 (1H, d, J=10.8 Hz), 5.40-5.56(2H, m), 5.87 (1H, d, J=14.8 Hz), 6.13 (1H, d, J=10.8 Hz), 6.52 (1H, dd,J=10.8, 15.2 Hz), 6.86 (2H, d, J=6.4 Hz), 8.12 (2H, d, J=6.4 Hz); ESI-MSm/z 684 (M+H)⁺.

Example 37(8E,12E,14E)-7-((4-cyclohexylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 37)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.8 Hz), 0.89(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.4 Hz), 1.00 (3H, d, J=6.4 Hz),1.08-1.41 (8H, m), 1.34 (3H, s), 1.41-1.70 (6H, m), 1.70-1.98 (6H, m)1.77 (3H, s), 2.25-2.35 (1H, m), 2.42 (1H, dd, J=5.4, 14.2 Hz),2.50-2.63 (6H, m), 2.66 (1H, dd, J=2.2, 7.8 Hz), 2.89 (1H, dt, J=2.2,5.6 Hz), 3.37-3.55 (5H, m), 3.74-3.82 (1H, m), 4.75-4.82 (1H, m), 5.02(1H, d, J=10.8 Hz), 5.40-5.54 (2H, m), 5.86 (1H, d, J=15.2 Hz), 6.12(1H, d, J=10.8 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 689(M+H)⁺.

Example 38(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(tetrahydropyran-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 38)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.8 Hz), 0.89(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.4 Hz), 1.00 (3H, d, J=6.4 Hz),1.20-1.98 (14H, m), 1.34 (3H, s), 1.77 (3H, s), 2.38-2.62 (8H, m), 2.66(1H, dd, J=2.2, 7.8 Hz), 2.89 (1H, dt, J=2.2, 5.6 Hz), 3.37-3.56 (7H,m), 3.74-3.82 (1H, m), 3.94-4.02 (2H, m) 4.76-4.82 (1H, m), 5.02 (1H, d,J=10.4 Hz), 5.40-5.54 (2H, m), 5.86 (1H, d, J=15.2 Hz), 6.12 (1H, d,J=10.0 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 691 (M+H)⁺.

Example 39(8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 39)

(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(31 mg, 0.034 mmol) obtained in the Example 30-3 step was dissolved intetrahydrofuran (2 mL). Then, 1-isopropyl homopiperazine (9.7 mg, 0.068mmol) and triethylamine (10.3 mg, 0.10 mmol) were added to the mixture,and the reaction mixture was stirred under nitrogen atmosphere at roomtemperature for two hours. The reaction mixture was diluted with ethylacetate, and then the organic layer was washed with aqueous solution ofsodium hydrogencarbonate and brine. The resulting organic layer wasdried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (Fuji Silysia NH Silica gel; ethyl acetate-hexane,20:80→25:75) to give(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(26 mg, 0.028 mmol). ESI-MS m/z 919 (M+H)⁺.

This product (25 mg, 0.027 mmol) was dissolved in tetrahydrofuran (1mL), and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran,0.081 mL, 0.081 mmol) was added dropwise to the mixture. The reactionmixture was stirred under nitrogen atmosphere at room temperature fortwo hours. The reaction mixture was diluted with ethyl acetate, and thenthe organic layer was washed with aqueous solution of sodiumhydrogencarbonate and brine. The resulting organic layer was dried overanhydrous magnesium sulfate, filtered and concetrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (Fuji Silysia NH Silica gel; methylene chloride-methanol,100:0.5→100:2) to give the title compound (14.6 mg) as a colorless oil.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): (CD₃OD, 400 MHz) δ (ppm): 0.88(3H, d, J=6.8 Hz), 0.89 (3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.4 Hz),0.99-1.05 (9H, m), 1.16-2.00 (12H, m), 1.34 (3H, s), 1.77 (3H, s), 2.42(1H, dd, J=5.2, 14.0 Hz), 2.48-2.76 (7H, m), 2.84-2.98 (2H, m),3.38-3.58 (5H, m), 3.74-3.82 (1H, m), 4.76-4.91 (1H, m), 5.02 (1H, d,J=10.8 Hz), 5.40-5.56 (2H, m), 5.86 (1H, d, J=15.2 Hz), 6.12 (1H, d,J=10.0 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 663 (M+H)⁺.

Example 40(8E,12E,14E)-3,16,21-trihydroxy-7-(1-(4-(4-hydroxypiperidin-1-yl)piperidin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 40)

The title compound (colorless oil) was synthesized in the same manner asin Example 30.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): (CD₃OD, 400 MHz) δ (ppm): 0.87(3H, d, J=6.8 Hz), 0.89 (3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.4 Hz), 0.99(3H, d, J=6.4 Hz), 1.20-1.70 (12H, m), 1.34 (3H, s), 1.77 (3H, s),1.82-1.98 (6H, m), 2.29-2.38 (2H, m), 2.38-2.60 (4H, m), 2.66 (1H, dd,J=7.6, 2.0 Hz), 2.70-2.91 (5H, m), 3.49-3.55 (1H, m), 3.55-3.64 (1H, m),3.74-3.81 (1H, m), 4.11-4.20 (2H, m), 4.75-4.81 (1H, m), 5.02 (1H, d,J=10.8 Hz), 5.40-5.54 (2H, m), 5.86 (1H, d, J=15.2 Hz), 6.12 (1H, d,J=10.8 Hz), 6.52 (1H, dd, J=11.2, 15.6 Hz); ESI-MS m/z 705 (M+H)⁺.

Example 41(8E,12E,14E)-3,16,21-trihydroxy-7-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 41)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=6.0 Hz), 0.89(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.3 Hz), 0.99 (3H, d, J=6.8 Hz),1.18-1.69 (11H, m), 1.77 (3H, s), 1.86 (1H, dd, J=5.6, 14.0 Hz),1.88-1.98 (1H, m), 2.35-2.61 (9H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz),2.82-2.92 (1H, m), 3.38-3.55 (5H, m), 3.60-3.80 (3H, m), 4.70-4.86 (1H,covered with H₂O), 5.01 (1H, d, J=10.8 Hz), 5.34-5.54 (2H, m), 5.86 (1H,d, J=15.2 Hz), 6.12 (1H, d, J=10.8 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz);ESI-MS m/z 651 (M+H)⁺.

Example 42(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(morpholin-4-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 42)

The title compound (colorless oil) was synthesized in the same manner asin Example 18.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.2 Hz), 0.89(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 0.99 (3H, d, J=7.2 Hz),1.20-1.69 (13H, m), 1.77 (3H, s), 1.82-1.98 (4H, m), 2.33-2.46 (3H, m),2.50-2.60 (4H, m), 2.66 (1H, dd, J=2.0, 8.0 Hz), 2.72-2.86 (1H, m), 2.89(1H, dt, J=2.0, 6.4 Hz), 3.52 (1H, dt, J=4.0, 8.0 Hz), 3.68 (4H, dd,J=4.8, 4.8 Hz), 3.73-3.82 (1H, m), 4.09-4.21 (4H, m), 4.70-4.85 (1H, m),5.01 (1H, d, J=10.8 Hz), 5.40-5.55 (2H, m), 5.86 (1H, d, J=15.6 Hz),6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.6 Hz); ESI-MS m/z 691(M+H)⁺.

Example 43(8E,12E,14E)-7-((4-ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 43)

(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(40 mg, 0.044 mmol) obtained in the Example 30-3 step was dissolved intetrahydrofuran (2 mL). Then, 1-ethyl homopiperazine (11 mg, 0.088 mmol)and triethylamine (0.061 mL, 0.44 mmol) were added to the mixture, andthe reaction mixture was stirred under nitrogen atmosphere at roomtemperature overnight. The reaction mixture was diluted with ethylacetate, and then the organic layer was washed with water and brine. Theresulting organic layer was dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (Kanto Silica gel 60N,40 to 50 μm; ethyl acetate-hexane, 1:1→methylene chloride-methanol, 1:9)to give(8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-7-((4-ethylhomopiperazin-1-yl)carbonyl)oxy-16-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(34 mg, 0.038 mmol) as a colorless oil.

This product (34 mg, 0.038 mmol) was dissolved in tetrahydrofuran (1mL), and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran,0.187 mL, 0.187 mmol) was added dropwise to the mixture. The reactionmixture was stirred under a nitrogen atmosphere at room temperature for17 hours. The reaction mixture was diluted with ethyl acetate, and thenthe organic layer was washed with aqueous solution of sodiumhydrogencarbonate and brine. The resulting organic layer was dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (Kanto silica gel 60N, 40 to 50 μm; methylenechloride-methanol, 100:1.5→methylene chloride-methanol-28% ammoniumhydroxide aqueous solution, 100:5:1) to give the title compound (23.3mg) as a colorless oil.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=7.2 Hz), 0.89(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 1.01 (3H, d, J=6.8 Hz), 1.09(3H, t, J=7.2 Hz), 1.20-1.69 (11H, m), 1.77 (3H, s), 1.82-1.90 (3H, m),1.90-1.98 (1H, m), 2.42 (1H, dd, J=5.2, 14.0 Hz), 2.52-2.72 (9H, m),2.89 (1H, dt, J=2.4, 6.4 Hz), 3.42-3.60 (5H, m), 3.75-3.82 (1H, m),4.70-4.90 (1H, covered with H₂O), 5.02 (1H, d, J=10.8 Hz), 5.40-5.55(2H, m), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd,J=11.2, 15.2 Hz); ESI-MS m/z 649 (M+H)⁺.

Example 44(8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14.-trien-11-olide(compound 44)

The title compound (colorless oil) was synthesized in the same manner asin Example 30.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.88 (3H, d, J=6.4 Hz), 0.89(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.00 (3H, d, J=6.8 Hz), 1.07(6H, d, J=6.4 Hz), 1.20-1.69 (11H, m), 1.77 (3H, brs), 1.86 (1H, dd,J=5.2, 14.0 Hz), 1.89-1.98 (1H, m), 2.42 (1H, dd, J=5.2, 14.0 Hz),2.48-2.60 (6H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.67-2.78 (1H, m), 2.89(1H, dt, J=2.4, 6.0 Hz), 3.40-3.57 (5H, m), 3.74-3.82 (1H, m), 4.77-4.91(1H, covered with H₂O), 5.01 (1H, d, J=10.4 Hz), 5.40-5.55 (2H, m), 5.86(1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.52 (1H, dd, J=11.2, 15.2Hz); ESI-MS m/z 649 (M+H)⁺.

Example 45(8E,12E,14E)-7-((4-cyclopropylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 45)

The title compound (colorless oil) was synthesized in the same manner asin Example 30.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.32-0.54 (4H, m), 0.87 (3H,d, J=8.0 Hz), 0.90 (3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 1.00 (3H,d, J=6.0 Hz), 1.14-2.00 (19H, m), 2.42 (1H, dd, J=5.6, 14.0 Hz),2.42-2.62 (2H, m), 2.66 (1H, dd, J=2.0, 8.0 Hz), 2.70-2.92 (5H, m),3.37-3.58 (5H, m), 3.68-3.82 (1H, m), 4.77-4.91 (1H, covered with H₂O),5.01 (1H, d, J=10.8 Hz), 5.44-5.55 (2H, m), 5.86 (1H, d, J=15.2 Hz),6.13 (1H, d, J=10.8 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 661(M+H)⁺.

Example 46(8E,12E,14E)-7-((4-cyclopropylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 46)

The title compound (colorless oil) was synthesized in the same manner asin Example 30.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.40-0.52 (4H, m), 0.87 (3H,d, J=5.6 Hz), 0.89 (3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 0.98 (3H,d, J=6.0 Hz), 1.20-1.70 (12H, m), 1.77 (3H, s), 1.86 (1H, dd, J=5.2,14.0 Hz), 1.89-1.98 (1H, m), 2.42 (1H, dd, J=5.6, 14.0 Hz), 2.50-2.63(6H, m), 2.66 (1H, dd, J=2.0, 8.0 Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz),3.36-3.49 (4H, m), 3.52 (1H, dt, J=4.8, 7.6 Hz), 3.74-3.82 (1H, m),4.77-4.90 (1H, covered with H₂O), 5.01 (1H, d, J=10.4 Hz), 5.44-5.55(2H, m), 5.86 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd,J=11.2, 15.2 Hz); ESI-MS m/z 647 (M+H)⁺, 670 (M+Na)⁺.

Example 47(8E,12E,14E)-3,16,21-trihydroxy-7-((N-(4-hydroxy-1-methylpiperidin-4-yl)methyl-N-methyl)carbamoyloxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 47)

The title compound (colorless oil) was synthesized in the same manner asin Example 30.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.86 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 1.01 (3H, d, J=6.8 Hz),1.20-1.70 (15H, m), 1.77 (3H, s), 1.86 (1H, dd, J=5.2, 14.0 Hz),1.89-1.98 (1H, m), 2.27 (1.5H, s), 2.28 (1.5H, s), 2.34-2.46 (3H, m),2.50-2.64 (6H, m), 2.66 (1H, dd, J=2.0, 8.0 Hz), 2.89 (1H, dt, J=2.4,6.4 Hz), 3.01 (l.5H, s), 3.02 (1.5H, s), 3.52 (1H, dt, J=4.8, 8.0 Hz),3.74-3.82 (1H, m), 4.74-4.92 (1H, covered with H₂O), 5.01 (1H, d, J=10.4Hz), 5.40-5.55 (2H, m), 5.86 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 679 (M+H)⁺.

Example 48(8E,12E,14E)-7-(((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 48)

The title compound (colorless oil) was synthesized in the same manner asin Example 30.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.92 (3H, d, J=6.8 Hz), 0.94(-3H, d, J=7.2 Hz), 0.98-(3H, t, J=7.2 Hz), 1.03 (1.5H, d, J=6.8 Hz),1.06 (1.5H, d, J=6.8 Hz), 1.10-1.22 (3H, m), 1.22-1.75 (8H, m), 1.38(3H, s), 1.76-2.03 (4H, m), 1.82 (3H, s), 2.47 (1H, dd, J=5.6, 14.4 Hz),2.54-2.77 (6H, m), 2.83-2.99 (2H, m), 3.22-3.33 (1H, m), 3.53-3.63 (2H,m), 3.65 (1H, brs), 3.79-3.88 (1H, m), 4.36 (0.5H, s), 4.39 (0.5H, s),4.77-4.91 (1H, m), 5.06 (1H, d, J=10.4 Hz), 5.45-5.63 (2H, m), 5.91 (1H,d, J=15.2 Hz), 6.18 (1H, d, J=10.8 Hz), 6.57 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 647 (M+H)⁺.

Example 49(8E,12E,14E)-3,16,21-trihydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 49)

The title compound (colorless oil) was synthesized in the same manner asin Example 30.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.92 (3H, d, J=7.6 Hz), 0.94(3H, d, J=7.2 Hz), 0.98 (3H, t, J=7.6 Hz), 1.03 (1.5H, d, J=7.2 Hz),1.06 (1.5H, d, J=7.2 Hz), 1.09-1.16 (6H, m), 1.21-1.75 (8H, m), 1.38(3H, s), 1.77-2.03 (4H, m), 1.82 (3H, s), 2.47 (1H, dd, J=5.6, 14.4 Hz),2.52-2.75 (5H, m), 2.94 (1H, dt, J=2.0, 6.0 Hz), 3.05-3.16 (1H, m),3.21-3.34 (1H, m), 3.51-3.65 (2H, m), 3.77-3.89 (2H, brs), 4.35 (0.5H,s), 4.38 (0.5H, s), 4.79-4.91 (1H, m), 5.06 (1H, d, J=10.8 Hz),5.45-5.61 (2H, m), 5.91 (1H, d, J=15.6 Hz), 6.17 (1H, d, J=10.8 Hz),6.57 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 661 (M+H)⁺.

Example 50(8E,12E,14E)-7-(N-(2-(N′,N′-dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 50)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.0 Hz), 0.89(3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 1.01 (3H, brd, J=6.2 Hz),1.19-1.68 (7H, m), 1.33 (3H, s), 1.65 (1H, dd, J=6.2, 13.9 Hz), 1.77(3H, d, J=1.1 Hz), 1.86 (1H, dd, J=6.2, 13.9 Hz), 1.89-1.98 (1H, m),2.27 (6H, s), 2.42 (1H, dd, J=5.5, 13.9 Hz), 2.45-2.60 (4H, m), 2.66(1H, dd, J=2.2, 7.7 Hz), 2.87-2.92 (4H, m), 3.37-3.42 (2H, m), 3.52 (1H,dt, J=4.8, 8.4 Hz), 3.74-3.81 (1H, m), 4.74-4.82 (1H, m), 5.01 (1H, d,J=10.6 Hz), 5.40-5.53 (2H, m), 5.86 (1H, d, J=15.4 Hz), 6.12 (1H, dd,J=1.1, 11.0 Hz), 6.52 (1H, d, J=11.0, 15.4 Hz); ESI-MS m/z 623 (M+H)⁺.

Example 51(8E,12E,14E)-7-(N-(2-(N′,N′-dimethylamino)ethyl)carbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 51)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.3 Hz), 0.89(3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 0.99 (3H, d, J=6.6 Hz),1.20-1.68 (7H, m), 1.33 (3H, s), 1.65 (1H, dd, J=6.2, 13.9 Hz), 1.77(3H, s), 1.83-1.91 (1H, m), 1.86 (1H, dd, J=6.2, 13.9 Hz), 2.25 (6H, s),2.39-2.46 (1H, m), 2.43 (2H, t, J=7.0 Hz), 2.52-2.60 (2H, m), 2.66 (1H,dd, J=2.2, 8.1 Hz), 2.89 (1H, dt, J=2.2, 6.2 Hz), 3.21 (2H, t, J=7.0Hz), 3.52 (1H, dt, J=4.4, 8.4 Hz), 3.73-3.81 (1H, m), 4.74 (1H, dd,J=9.5, 9.5 Hz), 5.01 (1H, d, J=10.6 Hz), 5.38-5.52 (2H, m), 5.86 (1H, d,J=15.0 Hz), 6.12 (1H, d, J=11.0 Hz), 6.52 (1H, d, J=11.0, 15.0 Hz);ESI-MS m/z 609 (M+H)⁺.

Example 52(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 52)

(1)(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 52-1)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.625 (6H, q, J=8.1 Hz), 0.634(6H, q, J=8.1 Hz), 0.65 (6H, q, J=8.1 Hz), 0.83 (3H, t, J=7.3 Hz), 0.85(3H, d, J=7.0 Hz), 0.89 (3H, d, J=7.0 Hz), 0.93-1.01 (30H, m), 1.15-1.32(2H, m), 1.39-1.63 (6H, m), 1.42 (3H, s), 1.75 (3H, s), 1.83-1.92 (1H,m), 1.93 (1H, dd, J=4.8, 13.9 Hz), 2.33 (1H, dd, J=6.2, 13.6 Hz),2.44-2.60 (8H, m), 2.61 (1H, dd, J=2.2, 8.1 Hz), 2.85-2.90 (1H, m), 2.92(3H, s), 3.38-3.49 (2H, m), 3.61-3.72 (4H, m), 3.74 (1H, dt, J=3.7,6.6H), 3.90-3.98 (1H, m), 4.72-4.81 (1H, m), 4.93 (1H, d, J=10.6 Hz),5.41-5.52 (2H, m), 5.82 (1H, d, J=15.0 Hz), 6.12 (1H, d, J=11.0 Hz),6.50 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 1008 (M+H)⁺.

(2)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 52)

The protective groups for the hydroxyl groups in the compound 52-1 wasdeprotected in the same manner as in Example 23 to synthesize the titlecompound (colorless oil).

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.0 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.01 (3H, d, J=7.0 Hz),1.19-1.65 (7H, m), 1.33 (3H, s), 1.65 (1H, dd, J=5.5, 14.3 Hz), 1.77(3H, d, J=1.1 Hz), 1.86 (1H, dd, J=5.5, 14.3 Hz), 1.89-1.98 (1H, m),2.42 (1H, dd, J=5.5, 13.9 Hz), 2.42-2.61 (8H, m), 2.66 (1H, dd, J=2.2,8.1 Hz), 2.86-2.94 (1H, m), 2.91 (3H, s), 3.34-3.48 (2H, m), 3.52 (1H,dt, J=4.8, 8.4 Hz), 3.63-3.71 (4H, m), 3.74-3.81 (1H, m), 4.74-4.83 (1H,m), 5.01 (1H, d, J=10.6 Hz), 5.41-5.54 (2H, m), 5.86 (1H, d, J=15.0 Hz),6.12 (1H, d, J=11.0 Hz), 6.52 (!H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 665(M+H)⁺.

Example 53(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(piperidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 53)

(1)(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(piperidin-1-yl)ethyl)carbamoyloxy)-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 53-1)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.59-0.68 (18H, m), 0.82 (3H,t, J=7.3 Hz), 0.85 (3H, d, J=7.0 Hz), 0.89 (3H, d, J=7.0 Hz), 0.95-1.02(30H, m), 1.15-1.63 (14H, m), 1.42 (3H, s), 1.75 (3H, s), 1.83-1.92 (1H,m), 1.93 (1H, dd, J=4.8, 13.9 Hz), 2.32 (1H, dd, J=6.2, 13.6 Hz),2.41-2.59 (8H, m), 2.61 (1H, dd, J=2.2, 8.1 Hz), 2.85-2.92 (4H, m),3.38-3.44 (2H, m), 3.74 (1H, dt, J=3.3, 7.0 Hz), 3.91-3.98 (1H, m),4.71-4.80 (1H, m), 4.93 (1H, d, J=10.6 Hz), 5.40-5.52 (2H, m), 5.82 (1H,d, J=15.4 Hz), 6.11 (1H, d, J=11.0 Hz), 6.50 (1H, dd, J=l1.0, 15.4 Hz);ESI-MS m/z 1006 (M+H)⁺.

(2)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(piperidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 53)

The protective groups for the hydroxyl groups in the compound 53-1 wasdeprotected in the same manner as in Example 23 to synthesize the titlecompound (colorless oil).

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.7 Hz), 0.89(3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 1.01 (3H, brd, J=6.2 Hz),1.19-1.68 (14H, m), 1.33 (3H, s), 1.77 (3H, d, J=1.1 Hz), 1.86 (1H, dd,J=5.5, 14.3 Hz), 1.89-1.97 (1H, m), 2.39-2.60 (9H, m), 2.66 (1H, dd,J=2.2, 8.1 Hz), 2.86-2.93 (1H, m), 2.90 (3H, s), 3.36-3.46 (2H, m), 3.52(1H, dt, J=4.8, 8.4 Hz), 3.74-3.81 (1H, m), 4.74-4.82 (1H, m), 5.01 (1H,d, J=10.6 Hz), 5.41-5.53 (2H, m), 5.86 (1H, d, J=15.4 Hz), 6.12 (1H, d,J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 663 (M+H)⁺.

Example 54(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 54)

(1)(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 54-1)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.59-0.68 (18H, m), 0.82 (3H,t, J=7.3 Hz), 0.85 (3H, d, J=7.0 Hz), 0.89 (3H, d, J=7.0 Hz), 0.95-1.02(30H, m), 1.15-1.31 (2H, m), 1.42 (3H, s), 1.39-1.63 (6H, m), 1.75 (3H,d, J=0.7 Hz), 1.75-1.93 (5H, m), 1.93 (1H, dd, J=4.8, 13.9 Hz), 2.32(1H, dd, J=6.2, 13.6 Hz), 2.50-2.69 (9H, m), 2.85-2.93 (4H, m),3.39-3.46 (2H, m), 3.74 (1H, dt, J=3.3, 6.6 Hz), 3.90-3.98 (1H, m),4.71-4.80 (1H, m), 4.93 (1H, d, J=10.6 Hz), 5.40-5.52 (2H, m), 5.82 (1H,d, J=15.0 Hz), 6.12 (1H, d, J=11.0 Hz), 6.50 (1H, dd, J=11.0, 15.0 Hz);ESI-MS m/z 992 (M+H)⁺.

(2)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 54)

The protective groups for the hydroxyl groups in the compound 54-1 wasdeprotected in the same manner as in Example 23 to synthesize the titlecompound (colorless oil).

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.0 Hz), 0.89(3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 1.01 (3H, brd, J=6.6 Hz),1.19-1.65 (7H, m), 1.33 (3H, s), 1.65 (1H, dd, J=5.5, 13.9 Hz), 1.77(3H, d, J=1.1 Hz), 1.77-1.84 (4H, m), 1.86 (1H, dd, J=5.5, 13.9 Hz),1.89-1.98 (1H, m), 2.42 (1H, dd, J=5.1, 14.3 Hz), 2.50-2.67 (8H, m),2.66 (1H, dd, J=2.2, 8.1 Hz), 2.86-2.93 (1H, m), 2.90 (3H, s), 3.39-3.45(2H, m), 3.52 (1H, dt, J=4.8, 8.1 Hz), 3.74-3.82 (1H, m), 4.74-4.83 (1H,m), 5.01 (1H, d, J=10.6 Hz), 5.41-5.53 (2H, m), 5.86 (1H, d, J=15.4 Hz),6.12 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 649(M+H)⁺.

Example 55(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 55)

(1)(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 55-1)

A solution of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (0.3 Msolution in N,N-dimethylformamide-chloroform (1:9), 80 μL, 24 μmol) intetrahydrofuran (0.5 mL) was added dropwise to a solution of(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(12.7 mg, 12.7 μmol) obtained in the Example 23-3 step intetrahydrofuran (0.5 mL) at room temperature. The reaction mixture wasstirred at room temperature for five hours, and then the solvent wasremoved by evaporation. The resulting residue was purified by silica gelcolumn chromatography (Fuji Silysia NH Silica gel; ethylacetate:hexane=1:2) to give the title compound (12.2 mg) as a colorlessoil.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.59-0.68 (18H, m), 0.82 (3H,t, J=7.7 Hz), 0.85 (3H, d, J=7.0 Hz), 0.89 (3H, d, J=7.0 Hz), 0.95-1.02(30H, m), 1.18-1.33 (2H, m), 1.39-1.63 (6H, m), 1.42 (3H, s), 1.72-1.98(4H, m), 1.75 (3H, d, J=1.1 Hz), 2.32 (1H, dd, J=6.2, 13.6 Hz), 2.38(1.5H, s), 2.40 (1.5H, s), 2.52-2.90 (6H, m), 3.19-3.28 (1H, m),3.44-3.52 (2H, m), 3.74 (1H, dt, J=3.3, 6.6 Hz), 3.90-3.97 (1H, m), 4.31(0.5H, s), 4.35 (0.5H, s), 4.71-4.79 (1H, m), 4.93 (1H, d, J=10.6 Hz),5.41-5.52 (2H, m), 5.82 (1H, d, J=15.4 Hz), 6.11 (1H, d, J=11.0 Hz),6.50 (1H, dd, J=11.0, 15.4 Hz); ESI-MS M/Z 976 (M+H)⁺.

(2)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-1-olide(compound 55)

(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olideobtained in the Example 55-1 step (12.2 mg, 12.5 μmol) was dissolved intetrahydrofuran (0.5 mL). Tetrabutylammonium fluoride (1.0 M solution intetrahydrofuran, 0.050 mL, 0.050 mmol) was dropwise to the mixture whilestirring at room temperature. The reaction mixture was stirred at roomtemperature for two hours, and then tetrabutylammonium fluoride (1.0 Msolution in tetrahydrofuran, 0.012 mL, 0.012 mmol) was further addeddropwise to the reaction mixture. The reaction mixture was furtherstirred for 30 minutes, and then methanol (50 μL) was added to thereaction mixture. This reaction mixture was purified by thin-layerchromatography (Fuji Silysia NH Silica gel plate; chloroform:methanol,40:1) to give the title compound (7.3 mg) as a colorless oil.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=6.6 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 0.98 (1.5H, d, J=7.0 Hz),1.01 (1.5H, d, J=7.0 Hz), 1.19-1.80 (9H, m), 1.33 (3H, s), 1.77 (3H, d,J=1.1 Hz), 1.83-1.97 (3H, m), 2.38-2.40 (1H, m), 2.38 (1.5H, s), 2.40(1.5H, s), 2.50-2.61 (1H, m), 2.56 (1H, dd, J=3.7, 14.3 Hz), 2.62-2.71(1H, m), 2.66 (1H, dd, J=2.2, 8.1 Hz), 2.75 (0.5H, dd, J=1.8, 10.3 Hz),2.81 (0.5H, dd, J=1.8, 10.3 Hz), 2.89 (1H, dt, J=2.2, 5.9 Hz), 3.20(0.5H, dd, J=1.8, 10.3 Hz), 3.25 (0.5H, dd, J=1.8, 10.3 Hz), 3.44-3.55(3H, m), 3.74-3.81 (1H, m), 4.31 (0.5H, s), 4.34 (0.5H, s), 4.74-4.82(1H, m), 5.01 (1H, d, J=10.6 Hz), 5.42-5.53 (2H, m), 5.86 (1H, d, J=15.4Hz), 6.12 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z633 (M+H)⁺.

Example 56(8E,12E,14E)-7-(N-(1-azabicyclo[2.2.2]octan-3-yl)carbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 56)

(1)(8E,12E,14E)-7-(N-(1-azabicyclo[2.2.2]octan-3-yl)carbamoyloxy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 56-1)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.59 (18H, m), 0.82 (3H, t,J=7.3 Hz), 0.85 (3H, d, J=7.0 Hz), 0.88 (3H, d, J=7.0 Hz), 0.95-1.01(30H, m), 1.18-1.89 (14H, m), 1.42 (3H, s), 1.74 (3H, s), 1.93 (1H, dd,J=4.8, 13.9 Hz), 2.32 (1H, dd, J=6.2, 13.2 Hz), 2.50-2.61 (3H, m), 2.61(1H, dd, J=2.2, 8.4 Hz), 2.72-2.91 (5H, m), 3.19-3.28 (1H, m), 3.66-3.78(2H, m), 3.90-3.97 (1H, m), 4.68-4.75 (1H, m), 4.93 (1H, d, J=10.6 Hz),5.38-5.50 (2H, m), 5.82 (1H, d, J=15.4 Hz), 6.11 (1H, d, J=11.0 Hz),6.49 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 990 (M+H)⁺.

(2)(8E,12E,14E)-7-(N-(1-azabicyclo[2.2.2]octan-3-yl)carbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 56)

The protective groups for the hydroxyl groups in the compound 56-1 weredeprotected in the same manner as in Example 23 to synthesize the titlecompound (colorless oil).

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.0 Hz), 0.89(3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 1.01 (3H, d, J=6.6 Hz),1.18-1.94 (15H, m), 1.33 (3H, s), 1.76 (3H, d, J=0.7 Hz), 2.42 (1H, dd,J=5.5, 14.3 Hz), 2.49-2.60 (3H, m), 2.66 (1H, dd, J=2.2, 8.1 Hz),2.69-2.92 (5H, m), 3.17-3.25 (1H, m), 3.52 (1H, dt, J=4.4, 8.4 Hz),3.64-3.70 (1H, m), 3.73-3.81 (1H, m), 4.70-4.79 (1H, m), 5.01 (1H, d,J=10.6 Hz), 5.39-5.51 (2H, m), 5.86 (1H, d, J=15.4 Hz), 6.12 (1H, d,J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 647 (M+H)⁺.

Example 57(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(N′-methylamino)cyclohexyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 57)

(1)(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-N-methyl-N-(2-(N′-methylamino)cyclohexyl)carbamoyloxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 57-1)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.59-0.69 (18H, m), 0.82 (3H,t, J=7.3 Hz), 0.85 (3H, d, J=7.0 Hz), 0.85-0.91 (3H, m), 0.95-1.03 (30H,m), 1.07-1.68 (13H, m), 1.42 (3H, s), 1.71-1.82 (2H, m), 1.75 (3H, s),1.83-1.94 (1H, m), 1.94 (1H, dd, J=4.8, 13.9 Hz), 2.08-2.16 (1H, m),2.29-2.36 (1H, m), 2.33 (3H, s), 2.47-2.61 (3H, m), 2.61 (1H, dd, J=2.2,8.1 Hz), 2.78 (3H, s), 2.85-2.90 (1H, m), 3.72-3.86 (2H, m), 3.91-3.97(1H, m), 4.78 (1H, dd, J=9.2, 9.2 Hz), 4.93 (1H, d, J=10.6 Hz),5.41-5.52 (2H, m), 5.82 (1H, d, J=15.0 Hz), 6.11 (1H, d, J=11.0 Hz),6.50 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 1006 (M+H)⁺.

(2)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(N′-methylamino)cyclohexyl)carbamoyloxy)-18,19-epoxytricosa-12,14-trien-11-olide(compound 57)

The protective groups for the hydroxyl groups in the compound 57-1 weredeprotected in the same manner as in Example 23 to synthesize the titlecompound (colorless oil).

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.86 (3H, brd, J=5.9 Hz), 0.89(3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 0.97-1.68 (16H, m), 1.33 (3H,s), 1.71-1.82 (2H, m), 1.76 (3H, d, J=0.7 Hz), 1.86 (1H, dd, J=5.5, 13.9Hz), 1.90-1.99 (1H, m), 2.07-2.16 (1H, m), 2.32 (3H, s), 2.42 (1H, dd,J=5.5, 13.9 Hz), 2.47-2.63 (3H, m), 2.66 (1H, dd, J=2.2, 8.1 Hz), 2.78(3H, s), 2.88 (1H, dt, J=2.2, 6.2 Hz), 3.52 (1H, dt, J=4.8, 8.1 Hz),3.74-3.82 (2H, m), 4.81 (1H, dd, J=9.9, 9.9 Hz), 5.01 (1H, d, J=10.6Hz), 5.42-5.53 (2H, m), 5.86 (1H, d, J=15.4 Hz), 6.12 (1H, d, J=11.0Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 663 (M+H)⁺.

Example 58(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 58)

(1)(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-(N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 58-1)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.59-0.68 (18H, m), 0.82 (3H,t, J=7.7 Hz), 0.85 (3H, d, J=6.6 Hz), 0.89 (3H, d, J=7.0 Hz), 0.95-1.02(30H, m), 1.16-1.32 (2H, m), 1.39-1.62 (6H, m), 1.42 (3H, s), 1.75 (3H,s), 1.75-1.87 (1H, m),-1.93 (1H, dd, J=4.8, 13.9 Hz), 2.32 (1H, dd,J=6.2, 13.6 Hz), 2.42-2.61 (8H, m), 2.61 (1H, dd, J=2.2, 8.4 Hz),2.85-2.90 (1H, m), 3.32 (2H, t, J=6.6 Hz), 3.67 (4H, t, J=4.8 Hz), 3.74(1H, dt, J=3.3, 6.6H), 3.90-3.98 (1H, m), 4.71 (1H, dd, J=8.8, 8.8 Hz),4.93 (1H, d, J=10.6 Hz), 5.37-5.50 (2H, m), 5.82 (1H, d, J=15.0 Hz),6.11 (1H, d, J=11.0 Hz), 6.49 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 994(M+H)⁺.

(2)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 58)

The protective groups for the hydroxyl groups in the compound 58-1 weredeprotected in the same manner as in Example 23 to synthesize the titlecompound (colorless oil).

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.0 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.00 (3H, d, J=7.0 Hz),1.19-1.64 (7H, m), 1.33 (3H, s), 1.65 (1H, dd, J=5.5, 13.9 Hz), 1.76(3H, d, J=0.7 Hz), 1.83-1.90 (1H, m), 1.86 (1H, dd, J=5.5, 13.9 Hz),2.38-2.60 (9H, m), 2.66 (1H, dd, J=2.2, 8.1 Hz), 2.88 (1H, dt, J=2.2,5.5 Hz), 3.23 (2H, dt, J=1.1, 7.0 Hz), 3.52 (1H, dt, J=4.8, 8.1 Hz),3.67 (4H, t, J=4.8 Hz), 3.73-3.80 (1H, m), 4.74 (1H, dd, J=9.9, 9.9 Hz),5.01 (1H, d, J=10.6 Hz), 5.38-5.51 (2H, m), 5.86 (1H, d, J=15.0 Hz),6.12 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 651(M+H)⁺.

Example 59(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(piperidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 59)

(1)(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-(N-(2-(piperidin-1-yl)ethyl)carbamoyloxy)-13,16,21-tris(triethylsiloxy)-8,19-epoxytricosa-8,12,14-trien-11-olide(compound 59-1)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.59-0.68 (18H, m), 0.82 (3H,t, J=7.7 Hz), 0.85 (3H, d, J=7.0 Hz), 0.89 (3H, d, J=6.6 Hz), 0.95-1.02(30H, m), 1.16-1.32 (2H, m), 1.39-1.62 (12H, m), 1.42 (3H, s), 1.74 (3H,s), 1.76-1.85 (1H, m), 1.93 (1H, dd, J=4.8, 13.9 Hz), 2.32 (1H, dd,J=6.6, 13.6 Hz), 2.41-2.61 (8H, m), 2.61 (1H, dd, J=2.2, 8.4 Hz),2.84-2.90 (1H, m), 3.23 (2H, t, J=7.0 Hz), 3.74 (1H, dt, J=3.7, 7.0 Hz),3.90-3.97 (1H, m), 4.70 (1H, dd, J=9.2, 9.2 Hz), 4.93 (1H, d, J=10.6Hz), 5.37-5.50 (2H, m), 5.82 (1H, d, J=15.4 Hz), 6.11 (1H, d, J=11.0Hz), 6.49 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 992 (M+H)⁺.

(2)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(piperidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 59)

The protective groups for the hydroxyl groups in the compound 59-1 weredeprotected in the same manner as in Example 23 to synthesize the titlecompound (colorless oil).

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.3 Hz), 0.89(3H, d, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 0.99 (3H, d, J=7.0 Hz),1.19-1.68 (14H, m), 1.33 (3H, s), 1.76 (3H, d, J=1.1 Hz), 1.83-1.90 (1H,m), 1.86 (1H, dd, J=5.5, 13.9 Hz), 2.38-2.60 (9H, .m), 2.66 (1H, dd,J=2.6, 8.1 Hz), 2.89 (1H, dt, J=2.6, 5.5 Hz), 3.23 (2H, dd, J=6.2, 7.7Hz), 3.52 (1H, dt, J=4.8, 8.4 Hz), 3.73-3.80 (1H, m), 4.74 (1H, dd,J=9.9, 9.9 Hz), 5.01 (1H, d, J=10.6 Hz), 5.38-5.51 (2H, m), 5.86 (1H, d,J=15.4 Hz), 6.12 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz);ESI-MS m/z 649 (M+H)⁺.

Example 60(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 60)

(1)(8E,12E,14E)-6,10,12,16,20-pentamethyl-7-(N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 60-1)

The title compound (colorless oil) was synthesized in the same manner asin Example 23.

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.59-0.68 (18H, m), 0.82 (3H,t, J=7.7 Hz), 0.85 (3H, d, J=7.0 Hz), 0.89 (3H, d, J=6.6 Hz), 0.95-1.02(30H, m), 1.15-1.30 (2H, m), 1.39-1.61 (6H, m), 1.42 (3H, s), 1.75 (3H,d, J=0.7 Hz), 1.75-1.85 (5H, m), 1.93 (1H, dd, J=4.8, 13.9 Hz), 2.32(1H, dd, J=6.6, 13.6 Hz), 2.50-2.62 (9H, m), 2.85-2.90 (1H, m), 3.24(2H, t, J=7.0 Hz), 3.74 (1H, dt, J=3.3, 7.0 Hz), 3.90-3.97 (1H, m), 4.71(1H, dd, J=9.5, 9.5 Hz), 4.93 (1H, d, J=10.6 Hz), 5.37-5.50 (2H, m),5.82 (1H, d, J=15.4 Hz), 6.11 (1H, d, J=11.0 Hz), 6.49 (1H, dd, J=11.0,15.4 Hz); ESI-MS m/z 978 (M+H)⁺.

(2)(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(compound 60)

The protective groups for the hydroxyl groups in the compound 60-1 weredeprotected in the same manner as in Example 23 to synthesize the titlecompound (colorless oil).

¹H-NMR spectrum (CD₃OD, 400 MHz) δ (ppm): 0.87 (3H, d, J=7.7 Hz), 0.89(3H, d, J=7.3 Hz), Q.93 (3H, t, J=7.3 Hz), 1.00 (3H, d, J=6.6 Hz),1.20-1.65 (7H, m), 1.33 (3H, s), 1.65 (1H, dd, J=5.5, 13.9 Hz), 1.76(3H, d, J=1.1 Hz), 1.76-1.90 (5H, m), 1.86 (1H, dd, J=5.5, 13.9 Hz),2.42 (1H, dd, J=5.1, 13.9 Hz), 2.49-2.63 (8H, m), 2.66 (1H, dd, J=2.2,8.1 Hz), 2.89 (1H, dt, J=2.2, 5.5 Hz), 3.24 (2H, t, J=7.3 Hz), 3.52 (1H,dt, J=4.8, 8.1 Hz), 3.74-3.81 (1H, m), 4.74 (1H, dd, J=9.9, 9.9 Hz),5.01 (1H, d, J=10.6 Hz), 5.38-5.51 (2H, m), 5.86 (1H, d, J=15.4 Hz),6.12 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 635(M+H)⁺.

1. A compound represented by the formula (I):

wherein W represents

and R³, R⁷, R¹⁶, R¹⁷, R²⁰, R²¹ and R^(21′), the same or different,independently represent 1) a hydrogen atom, 2) a hydroxyl group or oxogroup, provided that the oxo group is limited to an oxo group formed byR³ or R⁷ in combination with a carbon atom to which R³ or R⁷ is bonded,and an oxo group formed by R²¹ and R^(21′) together in combination withthe carbon atom to which R²¹ and R^(21′) are bonded, 3) a C₁ to C₂₂alkoxy group which may have a substituent, 4) an unsaturated C₂ to C₂₂alkoxy group which may have a substituent, 5) a C₇ to C₂₂ aralkyloxygroup which may have a substituent, 6) a 5-membered to 14-memberedheteroaralkyloxy group which may have a substituent, 7) RC(═Y)—O—,wherein Y represents an oxygen atom or sulfur atom, and R represents a)a hydrogen atom, b) a C₁ to C₂₂ alkyl group which may have asubstituent, c) an unsaturated C₂ to C₂₂ alkyl group which may have asubstituent, d) a C₆ to C₁₄ aryl group which may have a substituent, e)a 5-membered to 14-membered heteroaryl group which may have asubstituent, f) a C₇ to C₂₂ aralkyl group which may have a substituent,g) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent, h) a C₁ to C₂₂ alkoxy group which may have a substituent,i) an unsaturated C₂ to C₂₂ alkoxy group which may have a substituent,j) a C₆ to C₁₄ aryloxy group which may have a substituent, k) a C₃ toC₁₄ cycloalkyl group which may have a substituent, l) a 3-membered to14-membered non-aromatic heterocyclic group which may have a substituentor m) a 5-membered to 14-membered heteroaryloxy group which may have asubstituent, 8) R^(S1)R^(S2)R^(S3)SiO—, wherein R^(S1), R^(S2) andR^(S3), the same or different, independently represent a) a C₁ to C₆alkyl group or b) a C₆ to C₁₄ aryl group, 9) a halogen atom, 10)R^(N1)R^(N2)N—R^(M)—, wherein R^(M) represents a) a single bond, b)—CO—O—, c) —SO₂—O—, d) —CS—O— or e) —CO—NR^(N3)—, wherein R^(N3)represents a hydrogen atom or a C₁ to C₆ alkyl group which may have asubstituent, provided that, the leftmost bond in b) to e) is bonded tothe nitrogen atom, R^(N1) and R^(N2), the same or different,independently represent a) a hydrogen atom, b) a C₁ to C₂₂ alkyl groupwhich may have a substituent, c) an unsaturated C₂ to C₂₂ alkyl groupwhich may have a substituent, d) an aliphatic C₂ to C₂₂ acyl group whichmay have a substituent, e) an aromatic C₇ to C₁₅ acyl group which mayhave a substituent, f) a C₆ to C₁₄ aryl group which may have asubstituent, g) a 5-membered to 14-membered heteroaryl group which mayhave a substituent, h) a C₇ to C₂₂ aralkyl group which may have asubstituent, i) a C₁ to C₂₂ alkylsulfonyl group which may have asubstituent, j) a C₆ to C₁₄ arylsulfonyl group which may have asubstituent, k) a 3-membered to 14-membered non-aromatic heterocyclicgroup formed by R^(N1) and R^(N2) together in combination with thenitrogen atom to which R^(N1) and R^(N2) are bonded, wherein the3-membered to 14-membered non-aromatic heterocyclic group may have asubstituent, l) a 5-membered to 14-membered heteroaralkyl group whichmay have a substituent, m) a C₃ to C₁₄ cycloalkyl group which may have asubstituent or n) a 3-membered to 14-membered non-aromatic heterocyclicgroup which may have a substituent, 11) R^(N4)SO₂—O—, wherein R^(N4)represents a) a C₁ to C₂₂ alkyl group which may have a substituent, b) aC₆ to C₁₄ aryl group which may have a substituent, c) a C₁ to C₂₂ alkoxygroup which may have a substituent, d) an unsaturated C₂ to C₂₂ alkoxygroup which may have a substituent, e) a C₆ to C₁₄ aryloxy group whichmay have a substituent, f) a 5-membered to 14-membered heteroaryloxygroup which may have a substituent, g) a C₇ to C₂₂ aralkyloxy groupwhich may have a substituent or h) a 5-membered to 14-memberedheteroaralkyloxy group which may have a substituent, 12)(R^(N5)O)₂PO—O—, wherein R^(N5) represents a) a C₁ to C₂₂ alkyl groupwhich may have a substituent, b) an unsaturated C₂ to C₂₂ alkyl groupwhich may have a substituent, c) a C₆ to C₁₄ aryl group which may have asubstituent, d) a 5-membered to 14-membered heteroaryl group which mayhave a substituent, e) a C₇ to C₂₂ aralkyl group which may have asubstituent or f) a 5-membered to 14-membered heteroaralkyl group whichmay have a substituent, 13) (R^(N1)R^(N2)N)₂PO—O—, wherein R^(N1) andR^(N2) are the same as defined above or 14)(R^(N1)R^(N2)N)(R^(N5)O)PO—O—, wherein R^(N1), R^(N2) and R^(N5) are thesame as defined above; a pharmacologically acceptable salt thereof, or ahydrate of those.
 2. The compound according to claim 1 represented bythe formula (I-a):

wherein W is the same as defined above, and R^(3a), R^(7a), R^(16a),R^(17a), R^(20a), R^(21a) and R^(21a′), the same or different,independently represent 1) a hydrogen atom, 2) a hydroxyl group or oxogroup, provided that the oxo group is limited to an oxo group formed byR^(3a) or R^(7a) in combination with the carbon atom to which R^(3a) orR^(7a) is bonded, and an oxo group formed by R^(21a) and R^(21a′)together in combination with a carbon atom to which R^(21a) and R^(21a′)are bonded, 3) a C₁ to C₂₂ alkoxy group which may have a substituent, 4)R^(a)C(═Y^(a))—O—, wherein Y^(a) represents an oxygen atom or sulfuratom, and R^(a) represents a) a hydrogen atom, b) a C₁ to C₂₂ alkylgroup which may have a substituent, c) an unsaturated C₂ to C₂₂ alkylgroup which may have a substituent, d) a C₆ to C₁₄ aryl group which mayhave a substituent, e) a 5-membered to 14-membered heteroaryl groupwhich may have a substituent, f) a C₇ to C₂₂ aralkyl group which mayhave a substituent, g) a 5-membered to 14-membered heteroaralkyl groupwhich may have a substituent, h) a C₁ to C₂₂ alkoxy group which may havea substituent, i) an unsaturated C₂ to C₂₂ alkoxy group which may have asubstituent, j) a C₆ to C₁₄ aryloxy group which may have a substituent,k) a C₃ to C₁₄ cycloalkyl group which may have a substituent, l) a3-membered to 14-membered non-aromatic heterocyclic group which may havea substituent or m) a 5-membered to 14-membered heteroaryloxy groupwhich may have a substituent, 5) R^(aS1)R^(aS2)R^(aS3)SiO—, whereinR^(aS1), R^(aS2) and R^(aS3), the same or different, independentlyrepresent a) a C₁ to C₆ alkyl group or b) a C₆ to C₁₄ aryl group or 6)R^(aN1)R^(aN2)N—R^(aM)—, wherein R^(aM) represents a) —CO—O— or b)—CS—O—, provided that, in the leftmost bond a) or b) is bonded to thenitrogen atom, and R^(aN1) and R^(aN2), the same or different,independently represent a) a hydrogen atom, b) a C₁ to C₂₂ alkyl groupwhich may have a substituent, c) an unsaturated C₂ to C₂₂ alkyl groupwhich may have a substituent, d) an aliphatic C₂ to C₂₂ acyl group whichmay have a substituent, e) an aromatic C₇ to C₁₅ acyl group which mayhave a substituent, f) a C₆ to C₁₄ aryl group which may have asubstituent, g) a 5-membered to 14-membered heteroaryl group which mayhave a substituent, h) a C₇ to C₂₂ aralkyl group which may have asubstituent, i) a C₁ to C₂₂ alkylsulfonyl group which may have asubstituent, j) a C₆ to C₁₄ arylsulfonyl group which may have asubstituent, k) a 3-membered to 14-membered non-aromatic heterocyclicgroup formed by R^(aN1) and R^(aN2) together in combination with thenitrogen atom to which R^(aN1) and R^(aN2) are bonded, wherein the3-membered to 14-membered non-aromatic heterocyclic group may have asubstituent, l) a 5-membered to 14-membered heteroaralkyl group whichmay have a substituent, m) a C₃ to C₁₄ cycloalkyl group which may have asubstituent or n) a 3-membered to 14-membered non-aromatic heterocyclicgroup which may have a substituent; a pharmacologically acceptable saltthereof, or a hydrate of those.
 3. The compound according to claim 1represented by the formula (I-b):

wherein W is the same as defined above, and R^(3b), R^(7b), R^(16b),R^(17b), R^(20b), R^(21b) and R^(21′b), the same or different,independently represent 1) a hydrogen atom, 2) a hydroxyl group or oxogroup, provided that the oxo group is limited to an oxo group formed byR^(3b) or R^(7b) in combination with the carbon atom to which R^(3b) orR^(7b) is bonded, and an oxo group formed by R^(21b) and R^(21b′)together in combination with the carbon atom to which R^(21b) andR^(21b′) are bonded, 3) a C₁ to C₂₂ alkoxy group which may have asubstituent, 4) R^(b)C(═O)—O—, wherein R^(b) represents a) a C₁ to C₂₂alkyl group which may have a substituent, b) an unsaturated C₂ to C₂₂alkyl group which may have a substituent, c) a C₇ to C₂₂ aralkyl groupwhich may have a substituent, d) a 5-membered to 14-memberedheteroaralkyl group which may have a substituent, e) a C₆ to C₁₄ aryloxygroup which may have a substituent, f) a C₃ to C₁₄ cycloalkyl groupwhich may have a substituent or g) a 3-membered to 14-memberednon-aromatic heterocyclic group which may have a substituent, 5)R^(bS1)R^(bS2)R^(bS3)SiO—, wherein R^(bS1), R^(bS2) and R^(bS3), thesame or different, independently represent a) a C₁ to C₆ alkyl group orb) a C₆ to C₁₄ aryl group or 6) R^(bN1)R^(bN2)N—R^(bM)—, wherein R^(bM)represents a) —CO—O— or b) —CS—O—, provided that, the leftmost bond ina) or b) is bonded to the nitrogen atom, and R^(bN1) and R^(bN2), thesame or different, independently represent a) a hydrogen atom, b) a C₁to C₂₂ alkyl group which may have a substituent, c) a 3-membered to14-membered non-aromatic heterocyclic group formed by R^(bN1) andR^(bN2) together in combination with the nitrogen atom to which R^(bN1)and R^(bN2) are bonded, wherein the 3-membered to 14-memberednon-aromatic heterocyclic group may have a substituent, d) a C₃ to C₁₄cycloalkyl group which may have a substituent or e) a 3-membered to14-membered non-aromatic heterocyclic group which may have asubstituent; a pharmacologically acceptable salt thereof, or a hydrateof those.
 4. The compound according to claim 1 represented by theformula (I-c):

wherein W is the same as defined above, and R^(3c), R^(7c), R^(16c),R^(17c), R^(20c), R^(21c) and R^(21′c), the same or different,independently represent 1) a hydrogen atom, 2) a hydroxyl group or oxogroup, provided that the oxo group is limited to an oxo group formed byR^(3c) or R^(7c) in combination with the carbon atom to which R^(3c) orR^(7c) is bonded, and an oxo group formed by R^(21c) and R^(21c′)together in combination with the carbon atom to which R^(21c) andR^(21c′) are bonded, 3) R^(c)C(═O)—O—, wherein R^(c) represents a C₁ toC₂₂ alkyl group which may have a substituent, 4)R^(cS1)R^(cS2)R^(cS3)SiO—, wherein R^(cS1), R^(cS2) and R^(cS3), thesame or different, independently represent a) a C₁ to C₆ alkyl group orb) a C₆ to C₁₄ aryl group or 5) R^(cN1)R^(cN2)N—R^(cM)—, wherein R^(cM)represents —CO—O—, provided that the leftmost bond is bonded to thenitrogen atom, and R^(cN1) and R^(cN2), the same or different,independently represent a) a hydrogen atom, b) a C₁ to C₂₂ alkyl groupwhich may have a substituent, c) a 3-membered to 14-memberednon-aromatic heterocyclic group formed by R^(cN1) and R^(cN2) togetherin combination with the nitrogen atom to which R^(cN1) and R^(cN2) arebonded, wherein the 3-membered to 14-membered non-aromatic heterocyclicgroup may have a substituent, d) a C₃ to C₁₄ cycloalkyl group which mayhave a substituent or e) a 3-membered to 14-membered non-aromaticheterocyclic group which may have a substituent; a pharmacologicallyacceptable salt thereof, or a hydrate of those.
 5. The compoundaccording to claim 1 represented by the formula (I-d):

wherein R^(3d) and R^(16d), the same or different, independentlyrepresent 1) a hydroxyl group, 2) a C₁ to C₂₂ alkoxy group which mayhave a substituent, 3) an unsaturated C₂ to C₂₂ alkoxy group which mayhave a substituent, 4) a C₇ to C₂₂ aralkyloxy group which may have asubstituent, 5) R^(d)C(═O)—O—, wherein R^(d) represents a) a hydrogenatom, b) a C₁ to C₂₂ alkyl group which may have a substituent, c) anunsaturated C₂ to C₂₂ alkyl group which may have a substituent, d) a C₆to C₁₄ aryl group which may have a substituent, e) a 5-membered to14-membered heteroaryl group which may have a substituent, f) a C₇ toC₂₂ aralkyl group which may have a substituent, g) a 5-membered to14-membered heteroaralkyl group which may have a substituent, h) a C₁ toC₂₂ alkoxy group which may have a substituent, i) an unsaturated C₂ toC₂₂ alkoxy group which may have a substituent, j) a C₆ to C₁₄ aryloxygroup which may have a substituent or k) a 5-membered to 14-memberedheteroaryloxy group which may have a substituent or 6)R^(dN1)R^(dN2)N—CO—O—, wherein R^(dN1) and R^(dN2), the same ordifferent, independently represent a) a hydrogen atom, b) a C₁ to C₂₂alkyl group which may have a substituent, c) an unsaturated C₂ to C₂₂alkyl group which may have a substituent, d) a C₆ to C₁₄ aryl groupwhich may have a substituent, e) a 5-membered to 14-membered heteroarylgroup which may have a substituent, f) a C₇ to C₂₂ aralkyl group whichmay have a substituent, g) a 5-membered to 14-membered heteroaralkylgroup which may have a substituent, h) a C₃ to C₁₄ cycloalkyl groupwhich may have a substituent, i) a 3-membered to 14-memberednon-aromatic heterocyclic group which may have a substituent or j) a3-membered to 14-membered non-aromatic heterocyclic group formed byR^(dN1) and R^(dN2) together in combination with the nitrogen atom towhich R^(dN1) and R^(dN2) are bonded, wherein the 3-membered to14-membered non-aromatic heterocyclic group may have a substituent, andR^(7d) and R^(21d), the same or different, independently represent 1) ahydroxyl group, 2) a C₁ to C₂₂ alkoxy group which may have asubstituent, 3) an unsaturated C₂ to C₂₂ alkoxy group which may have asubstituent, 4) a C₇ to C₂₂ aralkyloxy group which may have asubstituent, 5) R^(d)C(═O)—O—, wherein R^(d) is the same as definedabove, 6) R^(dN1)R^(dN2)N—CO—O—, wherein R^(dN1) and R^(dN2) are thesame as defined above, 7) R^(dN1)R^(dN2)N—SO₂—O—, wherein R^(dN1) andR^(dN2) are the same as defined above, 8) R^(dN1)R^(dN2)N—CS—O—, whereinR^(dN1) and R^(dN2) are the same as defined above, 9) R^(dN4)—SO₂—O—,wherein R^(dN4) represents a) a C₁ to C₂₂ alkyl group which may have asubstituent, b) a C₆ to C₁₄ aryl group which may have a substituent, c)a C₁ to C₂₂ alkoxy group which may have a substituent, d) an unsaturatedC₂ to C₂₂ alkoxy group which may have a substituent, e) a C₆ to C₁₄aryloxy group which may have a substituent, f) a 5-membered to14-membered heteroaryloxy group which may have a substituent, g) a C₇ toC₂₂ aralkyloxy group which may have a substituent or h) a 5-membered to14-membered heteroaralkyloxy group which may have a substituent, 10)(R^(dN5)O)₂PO—O—, wherein R^(dN5) represents a) a C₁ to C₂₂ alkyl groupwhich may have a substituent, b) an unsaturated C₂ to C₂₂ alkyl groupwhich may have a substituent, c) a C₆ to C₁₄ aryl group which may have asubstituent, d) a 5-membered to 14-membered heteroaryl group which mayhave a substituent, e) a C₇ to C₂₂ aralkyl group which may have asubstituent or f) a 5-membered to 14-membered heteroaralkyl group whichmay have a substituent, 11) (R^(dN1)R^(dN2)N)₂PO—O—, wherein R^(dN1) andR^(dN2) are the same as defined above or 12)(R^(dN1)R^(dN2)N)(R^(dN5)O)PO—O—, wherein R^(dN1), R^(dN2) and R^(dN5)are the same as defined above; a pharmacologically acceptable saltthereof, or a hydrate of those.
 6. The compound according to claim 1,wherein R⁷ and/or R²¹ are independently represented by RC(═Y)—O—,wherein Y and R are the same as defined above or R^(N1)R^(N2)N—R^(M′)—,wherein R^(M′) represents a) —CO—O— or b) —CS—O—, provided that, theleftmost bond in a) or b) is bonded to the nitrogen atom, and R^(N1) andR^(N2) are the same as defined above; a pharmacologically acceptablesalt thereof, or a hydrate of those.
 7. The compound according to claim5 represented by the formula (I-e):

wherein R^(3e), R^(16e) and R^(21e), the same or different,independently represent 1) a hydroxyl group, 2) a C₁ to C₂₂ alkoxy groupwhich may have a substituent, 3) an unsaturated C₂ to C₂₂ alkoxy groupwhich may have a substituent, 4) a C₇ to C₂₂ aralkyloxy group which mayhave a substituent, 5) an aliphatic C₂ to C₆ acyl group which may have asubstituent or 6) R^(eN1)R^(eN2)N—CO—O—, wherein R^(eN1) and R^(eN2)independently represent a) a hydrogen atom or b) a C₁ to C₆ alkyl groupwhich may have a substituent, and R^(7e) represents R^(e)—C(═Y^(e))—O—,wherein Y^(e) represents an oxygen atom or sulfur atom, and R^(e)represents a) a hydrogen atom, b) a C₁ to C₂₂ alkyl group which may havea substituent, c) a C₆ to C₁₄ aryl group which may have a substituent,d) a 5-membered to 14-membered heteroaryl group which may have asubstituent, e) a C₇ to C₁₀ aralkyl group which may have a substituent,f) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent, g) a 3-membered to 14-membered non-aromatic heterocyclicgroup which may have a substituent h) a group of the formula (III):

wherein A) n represents an integer of 0 to 4, X_(e) represents i)—CHR^(eN4)—, ii) —NR^(eN5)—, iii) —O—, iv) —S—, v) —SO— or vi) —SO₂—,R^(eN1) represents i) a hydrogen atom or ii) a C₁ to C₆ alkyl groupwhich may have a substituent, R^(eN2) represents i) a hydrogen atom orii) a C₁ to C₆ alkyl group which may have a substituent, R^(eN3) andR^(eN4), the same or different, independently represent i) a hydrogenatom, ii) a C₁ to C₆ alkyl group which may have a substituent, iii) anunsaturated C₂ to C₁₀ alkyl group which may have a substituent, iv) a C₆to C₁₄ aryl group which may have a substituent, v) a 5-membered to14-membered heteroaryl group which may have a substituent, vi) a C₇ toC₁₀ aralkyl group which may have a substituent, vii) a C₃ to C₈cycloalkyl group which may have a substituent, viii) a C₄ to C₉cycloalkylalkyl group which may have a substituent, ix) a 5-membered to14-membered heteroaralkyl group which may have a substituent, x) a5-membered to 14-membered non-aromatic heterocyclic group which may havea substituent, xi) —NR^(eN6)R^(eN7), wherein R^(eN6) and R^(eN7), thesame or different, independently represent a hydrogen atom or a C₁ to C₆alkyl group which may have a substituent or xii) a 5-membered to14-membered non-aromatic heterocyclic group formed by R^(eN3) andR^(eN4) together in combination with the carbon atom to which R^(eN3)and R^(eN4) are bonded, wherein the 5-membered to 14-memberednon-aromatic heterocyclic group may have a substituent, and R^(eN5)represents i) a hydrogen atom, ii) a C₁ to C₆ alkyl group which may havea substituent, iii) an unsaturated C₂ to C₁₀ alkyl group which may havea substituent, iv) a C₆ to C₁₄ aryl group which may have a substituent,v) a 5-membered to 14-membered heteroaryl group which may have asubstituent, vi) a C₇ to C₁₀ aralkyl group which may have a substituent,vii) a C₃ to C₈ cycloalkyl group which may have a substituent, viii) aC₄ to C₉ cycloalkylalkyl group which may have a substituent, ix) a5-membered to 14-membered heteroaralkyl group which may have asubstituent, x) a 5-membered to 14-membered non-aromatic heterocyclicgroup which may have a substituent or xi) a 5-membered to 14-memberednon-aromatic heterocyclic group formed by R^(eN3) and R^(eN5) togetherin combination with the nitrogen atom to which R^(eN3) and R^(eN5) arebonded, wherein the 5-membered to 14-membered non-aromatic heterocyclicgroup may have a substituent, B) X_(e), n, R^(eN3), R^(eN4) and R^(eN5)independently represent the same group as defined above, and R^(eN1) andR^(eN2) independently represent a 5-membered to 14-membered non-aromaticheterocyclic group formed by R^(eN1) and R^(eN2) together, wherein the5-membered to 14-membered non-aromatic heterocyclic group may have asubstituent, C) X_(e), n, R^(eN2), R^(eN4) and R^(eN5) independentlyrepresent the same group as defined above, and R^(eN1) and R^(eN3)independently represent a 5-membered to 14-membered non-aromaticheterocyclic group formed by R^(eN1) and R^(eN3) together, wherein the5-membered to 14-membered non-aromatic heterocyclic group may have asubstituent or D) X_(e), n, R^(eN1), R^(eN4) and R^(eN5) independentlyrepresent the same group as defined above, and R^(eN2) and R^(eN3)independently represent a 5-membered to 14-membered non-aromaticheterocyclic group formed by R^(eN2) and R^(eN3) together, wherein the5-membered to 14-membered non-aromatic heterocyclic group may have asubstituent or i) a group of the formula (IV):

wherein R^(eN8) and R^(eN9), the same or different, independentlyrepresent i) a hydrogen atom, ii) a C₁ to C₆ alkyl group which may havea substituent, iii) a C₆ to C₁₄ aryl group which may have a substituent,iv) a 5-membered to 14-membered heteroaryl group which may have asubstituent, v) a C₇ to C₁₀ aralkyl group which may have a substituentor vi) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent; a pharmacologically acceptable salt thereof, or a hydrateof those.
 8. The compound according to claim 5, wherein R^(7e) and/orR^(21e) are independently represented by R^(e1)C(═Y^(e1))—O—, whereinY^(e1) represents an oxygen atom or sulfur atom, and R^(e1)represents 1) a hydrogen atom, 2) a C₁ to C₆ alkyl group which may havea substituent, 3) a C₆ to C₁₀ aryl group which may have a substituent,4) a 5-membered to 14-membered heteroaryl group which may have asubstituent, 5) a C₇ to C₁₀ aralkyl group which may have a substituentor 6) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent; a pharmacologically acceptable salt thereof, or a hydrateof those.
 9. The compound according to claim 5, wherein R^(7e) and/orR^(21e) are independently represented by R^(e2)C(═Y^(e2))—O—, whereinY^(e2) represents an oxygen atom or sulfur atom, and R^(e2) represents agroup of the formula (III′):

wherein A) n represents an integer of 0 to 4, X₁ represents 1)—CHR^(eN13)—, 2) —NR^(eN14)—, 3) —O—, 4) —S—, 5) —SO— or 6) —SO₂—,R^(eN10) and R^(eN11), the same or different, independently represent 1)a hydrogen atom or 2) a C₁ to C₆ alkyl group which may have asubstituent, R^(eN12) and R^(eN13), the same or different, independentlyrepresent 1) a hydrogen atom, 2) a C₁ to C₆ alkyl group which may have asubstituent, 3) an unsaturated C₂ to C₁₀ alkyl group which may have asubstituent, 4) a C₆ to C₁₄ aryl group which may have a substituent, 5)a 5-membered to 14-membered heteroaryl group which may have asubstituent, 6) a C₇ to C₁₀ aralkyl group which may have a substituent,7) a C₃ to C₈ cycloalkyl group which may have a substituent, 8) a C₄ toC₉ cycloalkylalkyl group which may have a substituent, 9) a 5-memberedto 14-membered heteroaralkyl group which may have a substituent, 10) a5-membered to 14-membered non-aromatic heterocyclic group which may havea substituent, 11) NR^(eN15)R^(eN16), wherein R^(eN15) and R^(eN16), thesame or different, independently represent a hydrogen atom or a C₁ to C₆alkyl group which may have a substituent, or 12) a 5-membered to14-membered non-aromatic heterocyclic group formed by R^(eN12) andR^(eN13) together, wherein the 5-membered to 14-membered non-aromaticheterocyclic group may have a substituent, and R^(eN14) represents 1) ahydrogen atom, 2) a C₁ to C₆ alkyl group which may have a substituent,3) an unsaturated C₂ to C₁₀ alkyl group which may have a substituent, 4)a C₆ to C₁₄ aryl group which may have a substituent, 5) a 5-membered to14-membered heteroaryl group which may have a substituent, 6) a C₇ toC₁₀ aralkyl group which may have a substituent, 7) a C₃ to C₈ cycloalkylgroup which may have a substituent, 8) a C₄ to C₉ cycloalkylalkyl groupwhich may have a substituent, 9) a 5-membered to 14-memberedheteroaralkyl group which may have a substituent, 10) a 5-membered to14-membered non-aromatic heterocyclic group which may have asubstituent, 11) a 5-membered to 14-membered non-aromatic heterocyclicgroup formed together by the nitrogen atom to which R^(eN14) is bonded,and one substituent selected from the group consisting of R^(eN10),R^(eN11) and R^(eN12), wherein the 5-membered to 14-memberednon-aromatic heterocyclic group may have a substituent or 12) a5-membered to 14-membered non-aromatic heterocyclic group formedtogether by the nitrogen atom to which R^(eN14) is bonded, and twosubstituents selected from the group consisting of R^(eN10), R^(eN11)and R^(eN12), wherein the 5-membered to 14-membered non-aromaticheterocyclic group may have a substituent or B) n, X₁, R^(eN11),R^(eN13) and R^(eN14) are the same as defined above, and R^(eN10) andR^(eN12) together form a 5-membered to 14-membered non-aromaticheterocyclic group, wherein the 5-membered to 14-membered non-aromaticheterocyclic group may have a substituent; a pharmacologicallyacceptable salt thereof, or a hydrate of those.
 10. The compoundaccording to claim 5, wherein X₁ represents —NR^(eN14)—, whereinNR^(eN14) is the same as defined above; a pharmacologically acceptablesalt thereof, or a hydrate of those.
 11. The compound according to claim5, wherein R^(7e) and/or R^(21e) independently representR^(e3)C(═Ye³)—O—, wherein Y^(e3) represents an oxygen atom or sulfuratom, and R^(e3) represents a group of the formula (V):

wherein n₁ represents an integer of 0 to 6, R^(eN17) represents 1) ahydrogen atom or 2) a C₁ to C₆ alkyl group which may have a substituent,and R^(eN18) represents 1) a hydrogen atom, 2) an amino group which mayhave a substituent, 3) a pyridyl group which may have a substituent, 4)a pyrrolidin-1-yl group which may have a substituent, 5) apiperidin-1-yl group which may have a substituent, 6) a morpholin-4-ylgroup which may have a substituent or 7) a piperazin-1-yl group whichmay have a substituent; a pharmacologically acceptable salt thereof, ora hydrate of those.
 12. The compound according to claim 5, whereinR^(7e) and/or R^(21e) independently represent R^(e4)CO—O—, whereinR^(e4) represents a group of the formula (VI):

wherein n₂ and n₃, the same or different, independently represent aninteger of 0 to 4, X₂ represents 1) —CHR^(eN21)—, 2) —NR^(eN22)—, 3)—O—, 4) —S—, 5) —SO— or 6) —SO₂—, R^(eN19) represents 1) a hydrogen atomor 2) a C₁ to C₆ alkyl group which may have a substituent, R^(eN20)represents 1) a hydrogen atom, 2) a C₁ to C₆ alkyl group which may havea substituent, 3) a C₆ to C₁₄ aryl group which may have a substituent or4) a C₇ to C₁₀ aralkyl group which may have a substituent, R^(eN21)represents 1) a hydrogen atom, 2) a C₁ to C₆ alkyl group which may havea substituent, 3) an unsaturated C₂ to C₁₀ alkyl group which may have asubstituent, 4) a C₆ to C₁₄ aryl group which may have a substituent, 5)a 5-membered to 14-membered heteroaryl group which may have asubstituent, 6) a C₇ to C₁₀ aralkyl group which may have a substituent,7) a C₃ to C₈ cycloalkyl group which may have a substituent, 8) a C₄ toC₉ cycloalkylalkyl group which may have a substituent, 9) a 5-memberedto 14-membered heteroaralkyl group which may have a substituent, 10)—NR^(eN23)R^(eN24), wherein R^(eN23) and R^(eN24), the same ordifferent, independently represent a hydrogen atom or a C₁ to C₆ alkylgroup which may have a substituent or 11) a 5-membered to 14-memberednon-aromatic heterocyclic group which may have a substituent, andR^(eN22) represents 1) a hydrogen atom, 2) a C₁ to C₆ alkyl group whichmay have a substituent, 3) an unsaturated C₂ to C₁₀ alkyl group whichmay have a substituent, 4) a C₆ to C₁₄ aryl group which may have asubstituent, 5) a 5-membered to 14-membered heteroaryl group which mayhave a substituent, 6) a C₇ to C₁₀ aralkyl group which may have asubstituent, 7) a C₃ to C₈ cycloalkyl group which may have asubstituent, 8) a C₄ to C₉ cycloalkylalkyl group which may have asubstituent, 9) a 5-membered to 14-membered heteroaralkyl group whichmay have a substituent or 10) a 5-membered to 14-membered non-aromaticheterocyclic group which may have a substituent; a pharmacologicallyacceptable salt thereof, or a hydrate of those.
 13. The compoundaccording to claim 5, wherein R^(7e) and/or R^(21e) independentlyrepresent R^(e5)CO—O—, wherein R^(e5) represents a group of the formula(VII):

wherein n₄ represents 1 or 2, R^(eN25) represents 1) a hydrogen atom or2) a C₁ to C₆ alkyl group which may have a substituent, and R^(eN26)represents 1) a hydrogen atom or 2) a C₁ to C₆ alkyl group which mayhave a substituent; a pharmacologically acceptable salt thereof, or ahydrate of those.
 14. The compound according to claim 5, wherein R^(7e)and/or R^(21e) independently represent R^(e6)CO—O—, wherein R^(e6)represents a group of the formula (VIII):

wherein n₂ and n₃, the same or different, independently represent aninteger of 0 to 4, X₃ represents 1) —CHR^(eN29)—, 2) —NR^(eN30)—, 3)—O—, 4) —S—, 5) —SO— or 6) —SO₂—, R^(eN27) represents 1) a hydrogen atomor 2) a C₁ to C₆ alkyl group which may have a substituent, R^(eN28)represents 1) a hydrogen atom, 2) a C₁ to C₆ alkyl group which may havea substituent, 3) a C₆ to C₁₄ aryl group which may have a substituent or4) a C₇ to C₁₀ aralkyl group which may have a substituent, R^(eN29)represents 1) a hydrogen atom, 2) a C₁ to C₆ alkyl group which may havea substituent, 3) an unsaturated C₂ to C₁₀ alkyl group which may have asubstituent, 4) a C₁ to C₆ alkoxy group which may have a substituent, 5)a C₆ to C₁₄ aryl group which may have a substituent, 6) a 5-membered to14-membered heteroaryl group which may have a substituent, 7) a C₇ toC₁₀ aralkyl group which may have a substituent, 8) a C₃ to C₈ cycloalkylgroup which may have a substituent, 9) a C₄ to C₉ cycloalkylalkyl groupwhich may have a substituent, 10) a 5-membered to 14-memberedheteroaralkyl group which may have a substituent, 11)—NR^(eN31)R^(eN32), wherein R^(eN31) and R^(eN32), the same ordifferent, independently represent a hydrogen atom or a C₁ to C₆ alkylgroup which may have a substituent, or form a 5-membered to 14-memberednon-aromatic heterocyclic group together with the nitrogen atom to whichR^(eN31) and R^(eN32) are bonded or 12) a 5-membered to 14-memberednon-aromatic heterocyclic group which may have a substituent, andR^(eN30) represents 1) a hydrogen atom, 2) a C₁ to C₆ alkyl group whichmay have a substituent, 3) an unsaturated C₂ to C₁₀ alkyl group whichmay have a substituent, 4) a C₆ to C₁₄ aryl group which may have asubstituent, 5) a 5-membered to 14-membered heteroaryl group which mayhave a substituent, 6) a C₇ to C₁₀ aralkyl group which may have asubstituent, 7) a C₃ to C₈ cycloalkyl group which may have asubstituent, 8) a C₄ to C₉ cycloalkylalkyl group which may have asubstituent, 9) a 5-membered to 14-membered heteroaralkyl group whichmay have a substituent or 10) a 5-membered to 14-membered non-aromaticheterocyclic group which may have a substituent; a pharmacologicallyacceptable salt thereof, or a hydrate of those.
 15. The compoundaccording to claim 5, wherein R^(7e) and/or R^(21e) independentlyrepresent R^(e7)CO—O—, wherein R^(e7) represents a group of the formula(IX):

wherein n₅ represents an integer of 1 to 3, and R^(eN33) represents 1)an amino group, 2) an amino group which may have a substituent, 3) apyrrolidin-1-yl group which may have a substituent, 4) a piperidin-1-ylgroup which may have a substituent or 5) a morpholin-4-yl group whichmay have a substituent; a pharmacologically acceptable salt thereof, ora hydrate of those.
 16. The compound according to claim 5, whereinR^(7e) and/or R^(21e) independently represent R^(e8)CO—O—, whereinR^(e8) represents a group

wherein n₅ represents an integer of 1 to 3, R^(eN34) represents 1) ahydrogen atom, 2) a C₁ to C₆ alkyl group which may have a substituent,3) a C₆ to C₁₄ aryl group which may have a substituent or 4) a C₇ to C₁₀aralkyl group which may have a substituent, and R^(eN35) represents 1) ahydrogen atom, 2) a C₁ to C₆ alkyl group which may have a substituent,3) a C₃ to C₈ cycloalkyl group which may have a substituent, 4) a3-membered to 8-membered non-aromatic heterocyclic group which may havea substituent, 5) a C₆ to C₁₄ aryl group which may have a substituent,6) a 5-membered to 14-membered heteroaryl group which may have asubstituent, 7) a C₇ to C₁₀ aralkyl group which may have a substituent,8) a 5-membered to 14-membered heteroaralkyl group which may have asubstituent or 9) a C₄ to C₉ cycloalkylalkyl group which may have asubstituent; a pharmacologically acceptable salt thereof, or a hydrateof those.
 17. The compound according to claim 5, wherein R^(7e) and/orR^(21e) independently represent R^(e9)CO—O—, wherein R^(e9) represents agroup of the formula (XI):

wherein n₅ represents an integer of 1 to 3, and R^(eN36) represents 1) ahydrogen atom, 2) a C₁ to C₆ alkyl group which may have a substituent,3) a C₃ to C₈ cycloalkyl group which may have a substituent, 4) a C₄ toC₉ cycloalkylalkyl group which may have a substituent, 5) a C₇ to C₁₀aralkyl group which may have a substituent, 6) a pyridyl group which mayhave a substituent or 7) a tetrahydropyranyl group which may have asubstituent; a pharmacologically acceptable salt thereof, or a hydrateof those.
 18. The compound according to claim 5, wherein R^(7e) and/orR^(21e) independently represent R^(e10)C—O—, wherein R^(e10) representsa group of the formula (XII):

wherein m₁, m₂, m₃, and m₄, the same or different, independentlyrepresent 0 or 1, n₅ represents an integer of 1 to 3, and R^(eN37)represents 1) a hydrogen atom, 2) a C₁ to C₆ alkyl group which may havea substituent, 3) an unsaturated C₂ to C₁₀ alkyl group which may have asubstituent, 4) a C₆ to C₁₄ aryl group which may have a substituent, 5)a 5-membered to 14-membered heteroaryl group which may have asubstituent, 6) a C₇ to C₁₀ aralkyl group which may have a substituent,7) a C₃ to C₈ cycloalkyl group which may have a substituent, 8) a C₄ toC₉ cycloalkylalkyl group which may have a substituent, 9) a 5-memberedto 14-membered heteroaralkyl group which may have a substituent or 10) a5-membered to 14-membered non-aromatic heterocyclic group which may havea substituent; a pharmacologically acceptable salt thereof, or a hydrateof those.
 19. The compound according to claim 5, wherein R^(7e) and/orR^(21e) independently represent R^(e11)CO—O—, wherein R^(e11) representsa group of the formula (XIII):

wherein m₅ represents an integer of 1 to 3, and n₅ represents 2 or 3; apharmacologically acceptable salt thereof, or a hydrate of those. 20.The compound according to claim 5, wherein R^(7e) and/or R^(21e)independently represent R^(e12)CO—O—, wherein R^(e12) represents a groupselected from a group consisting of:

group selected from a group consisting of

both of which may have a substituent on the ring; a pharmacologicallyacceptable salt thereof, or a hydrate of those.
 21. The compoundaccording to claim 1, wherein R¹⁶ is a hydroxyl group; apharmacologically acceptable salt thereof, or a hydrate of those. 22.The compound according to claim 1, wherein [1] W is

R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶, R¹⁷,R²⁰ and R^(21′) are a hydrogen atom, [2] W is

R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶, R¹⁷,R²⁰ and R^(21′) are a hydrogen atom, [3] W is

R³, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁷,R²⁰ and R^(21′) are a hydrogen atom, [4] W is

R²¹ and R^(21′) form an oxo group together with the carbon atom to whichR²¹ and R^(21′) are bonded, R³, R¹⁶ and R²⁰ are a hydroxyl group, R⁷ isan acetoxy group, and R¹⁷ is a hydrogen atom, [5] W is

R³, R¹⁶, R²⁰ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, andR¹⁷ and R^(21′) are a hydrogen atom, [6] W is

R³, R⁷, R¹⁶ and R²¹ are a hydroxyl group, and R¹⁷, R²⁰ and R^(21′) are ahydrogen atom, [7] W is

R³, R¹⁷, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, andR²⁰ and R^(21′) are a hydrogen atom or [8] W is

R²¹ and R^(21′) form an oxo group together with the carbon atom to whichR²¹ and R^(21′) are bonded, R³ and R¹⁶ are a hydroxyl group, R⁷ is anacetoxy group, and R¹⁷ and R²⁰ are a hydrogen atom; a pharmacologicallyacceptable salt thereof, or a hydrate of those.
 23. The compoundaccording to claim 1, which is(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-7-((4-ethylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-7-(N-(3-(N′,N′-dimethylamino)propyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-7-((4-(4-hydroxypiperidin-1-yl)piperidin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(morpholin-4-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-7-((4-ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-7-(N-(2-(N′,N′-dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-7-(N-(2-(N′,N′-dimethylamino)ethyl)carbamoyloxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olideor(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide.24. The compound according to claim 1, which is(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-7-((4-ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide,(8E,12E,14E)-3,16,21-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olideor(8E,12E,14E)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide.25. A medicine comprising the compound according to claim 1, apharmacologically acceptable salt thereof, or a hydrate of those as anactive ingredient.
 26. A pharmaceutical composition comprising thecompound according to claim 1, a pharmacologically acceptable saltthereof, or a hydrate of those as an active ingredient.
 27. The medicineaccording to claim 25 as an agent for preventing or treating a diseasefor which gene expression control is effective.
 28. The medicineaccording to claim 25 as an agent for preventing or treating a diseasefor which suppression of VEGF production is effective.
 29. The medicineaccording to claim 25 as an agent for preventing or treating a diseasefor which an antiangiogenic effect is effective.
 30. The medicineaccording to claim 25 as an angiogenesis inhibitor.
 31. The medicineaccording to claim 25 as an antitumor agent.
 32. The medicine accordingto claim 25 as a therapeutic agent for treating hemangioma.
 33. Themedicine according to claim 25 as a cancer metastasis inhibitor.
 34. Themedicine according to claim 25 as a therapeutic agent for treatingretinal neovascularization or diabetic retinopathy.
 35. The medicineaccording to claim 25 as a therapeutic agent for treating inflammatorydisease.
 36. The medicine according to claim 25 as a therapeutic agentfor inflammatory diseases consisting of deformant arthritis, rheumatoidarthritis, psoriasis, and delayed hypersensitive reaction.
 37. Themedicine according to claim 25 as a therapeutic agent for treatingatherosclerosis.
 38. The medicine according to claim 25 as a therapeuticagent for treating a solid cancer.
 39. The medicine according to claim38, wherein the solid tumor is lung cancer, brain tumor, breast cancer,prostate cancer, ovarian cancer, colon cancer or melanoma.
 40. Themedicine according to claim 25 as a therapeutic agent for treatingleukemia.
 41. The medicine according to claim 25 as an antitumor agentbased on gene expression control.
 42. The medicine according to claim 25as an antitumor agent based on suppression of VEGF production.
 43. Themedicine according to claim 25 as an antitumor agent based on an effectof angiogenesis inhibition.
 44. A method for preventing or treating adisease for which gene expression control is effective, comprisingadministering a pharmacologically effective dose of the medicineaccording to claim 25 to a patient.
 45. A method for preventing ortreating a disease for which suppression of VEGF production iseffective, comprising administering a pharmacologically effective doseof the medicine according to claim 25 to a patient.
 46. A method forpreventing or treating a disease for which angiogenesis inhibition iseffective, comprising administering a pharmacologically effective doseof the medicine according to claim 25 to a patient.
 47. Use of thecompound according to claim 1, a pharmacologically acceptable saltthereof or a hydrate of those, for manufacturing an agent for preventingor treating a disease for which gene expression control is effective.48. Use of the compound according to claim 1, a pharmacologicallyacceptable salt thereof or a hydrate of those, for manufacturing anagent for preventing or treating a disease for which suppression of VEGFproduction is effective.
 49. Use of the compound according to claim 1, apharmacologically acceptable salt thereof or a hydrate of those, formanufacturing an agent for preventing or treating a disease for whichangiogenesis inhibition is effective.
 50. Use of the compound accordingto claim 1, a pharmacologically acceptable salt thereof or a hydrate ofthose, for manufacturing an agent for preventing or treating a solidcancer.
 51. A method for producing a 6-deoxy 11107 compound,characterized in that the method comprises culturing a microorganismbelonging to the genus Streptomyces which is capable of producing acompound of the formula (I):

wherein [1] W is

R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶, R¹⁷,R²⁰ and R^(21′) are a hydrogen atom or [2] W is

R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶, R¹⁷,R²⁰ and R^(21′) are a hydrogen atom; and collecting the compound asdefined in [1] or [2] (hereinafter referred to as “6-deoxy 11107compound”) from the culture.
 52. Streptomyces sp. strain A-1543 (FERMBP-8442) that is capable of producing the 6-deoxy 11107 compoundaccording to claim
 51. 53. A method for producing a 6-deoxy compound bybiologically converting a compound of the formula (I):

wherein [1] W is

R³ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁶, R¹⁷,R²⁰ and R^(21′) are a hydrogen atom (hereinafter referred to as “6-deoxy11107B”) into a compound of the formula (I), wherein [3] W is

R³, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, and R¹⁷,R²⁰ and R^(21′) are a hydrogen atom, [4] W is

R²¹ and R^(21′) form an oxo group together with the carbon atom to whichR²⁰ and R^(21′) are bonded, R³, R¹⁶ and R²⁰ are a hydroxyl group, R⁷ isan acetoxy group, and R¹⁷ is a hydrogen atom, [5] W is

R³, R¹⁶, R²⁰ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, andR¹⁷ and R^(21′) are a hydrogen atom, [6] W is

R³, R⁷, R¹⁶ and R²¹ are a hydroxyl group, and R¹⁷, R²⁰ and R^(21′) are ahydrogen atom, [7] W is

R³, R¹⁷, R¹⁶ and R²¹ are a hydroxyl group, R⁷ is an acetoxy group, andR²⁰ and R^(21′) are a hydrogen atom or [8] W is

R²¹ and R^(21′) form an oxo group together with the carbon atom to whichR²¹ and R^(21′) are bonded, R³ and R¹⁶ are a hydroxyl group, R⁷ is anacetoxy group, and R¹⁷ and R²⁰ are a hydrogen atom (these compounds arehereinafter referred to as “6-deoxy compounds”), comprising 1) a stepthat can conduct the biological conversion, the step of incubating6-deoxy 11107B in the presence of a culture solution of a strainselected from microorganisms belonging to bacteria or a product preparedfrom culture cells of the strain, and 2) collecting a 6-deoxy compoundfrom the incubated solution.
 54. The method according to claim 53,wherein the microorganism belonging to bacteria is strain A-1544 (FERMBP-8446) or strain A-1545 (FERM BP-8447).
 55. Strain A-1544 (FERMBP-8446) or strain A-1545 (FERM BP-8447) which is capable of converting6-deoxy 11107B into a 6-deoxy compound.